Stem Cell Investig. 2020; 7: 8.

1Department of Basic Dental Science, National Research Centre, Cairo, Egypt;

2Stem Cell Laboratory, Center of Excellence for Advanced Sciences, National Research Centre, Cairo, Egypt

1Department of Basic Dental Science, National Research Centre, Cairo, Egypt;

2Stem Cell Laboratory, Center of Excellence for Advanced Sciences, National Research Centre, Cairo, Egypt

Received 2020 Jan 3; Accepted 2020 Apr 30.

Recent research reporting successful translation of stem cell therapies to patients have enriched the hope that such regenerative strategies may one day become a treatment for a wide range of vexing diseases. In fact, the past few years witnessed, a rather exponential advancement in clinical trials revolving around stem cell-based therapies. Some of these trials resulted in remarkable impact on various diseases. In this review, the advances and challenges for the development of stem-cell-based therapies are described, with focus on the use of stem cells in dentistry in addition to the advances reached in regenerative treatment modalities in several diseases. The limitations of these treatments and ongoing challenges in the field are also discussed while shedding light on the ethical and regulatory challenges in translating autologous stem cell-based interventions, into safe and effective therapies.

Keywords: Stem cells, therapies, clinical trials, translation

Cell-based therapy as a modality of regenerative medicine is considered one of the most promising disciplines in the fields of modern science & medicine. Such an advanced technology offers endless possibilities for transformative and potentially curative treatments for some of humanities most life threatening diseases. Regenerative medicine is rapidly becoming the next big thing in health care with the particular aim of repairing and possibly replacing diseased cells, tissues or organs and eventually retrieving normal function. Fortunately, the prospect of regenerative medicine as an alternative to conventional drug-based therapies is becoming a tangible reality by the day owing to the vigorous commitment of the research communities in studying the potential applications across a wide range of diseases like neurodegenerative diseases and diabetes, among many others (1).

Recent research reporting successful translation of stem cell therapies to patients have enriched the hope that such regenerative strategies may one day become a treatment for a wide range of vexing diseases (2). In fact, the past few years witnessed, a rather exponential advancement in clinical trials revolving around stem cell-based therapies. Some of these trials resulted in remarkable impact on various diseases (3). For example, a case of Epidermolysis Bullosa manifested signs of skin recovery after treatment with keratinocyte cultures of epidermal stem cells (4). Also, a major improvement in eyesight of patients suffering from macular degeneration was reported after transplantation of patient-derived induced pluripotent stem cells (iPSCs) that were induced to differentiate into pigment epithelial cells of the retina (5).

However, in spite of the increased amount of publications reporting successful cases of stem cell-based therapies, a major number of clinical trials have not yet acquired full regulatory approvals for validation as stem cell therapies. To date, the most established stem cell treatment is bone marrow transplants to treat blood and immune system disorders (1,6,7).

In this review, the advances and challenges for the development of stem-cell-based therapies are described, with focus on the use of stem cells in dentistry in addition to the advances reached in regenerative treatment modalities in several diseases. The limitations of these treatments and ongoing challenges in the field are also discussed while shedding light on the ethical and regulatory challenges in translating autologous stem cell-based interventions, into safe and effective therapies.

Stem cell-based therapies are defined as any treatment for a disease or a medical condition that fundamentally involves the use of any type of viable human stem cells including embryonic stem cells (ESCs), iPSCs and adult stem cells for autologous and allogeneic therapies (8). Stem cells offer the perfect solution when there is a need for tissue and organ transplantation through their ability to differentiate into the specific cell types that are required for repair of diseased tissues.

However, the complexity of stem cell-based therapies often leads researchers to search for stable, safe and easily accessible stem cells source that has the potential to differentiate into several lineages. Thus, it is of utmost importance to carefully select the type of stem cells that is suitable for clinical application (7,9).

There are mainly three types of stem cells. All three of them share the significant property of self-renewal in addition to a unique ability to differentiate. However, it should be noted that stem cells are not homogeneous, but rather exist in a developmental hierarchy (10). The most basic and undeveloped of stem cells are the totipotent stem cells. These cells are capable of developing into a complete embryo while forming the extra-embryonic tissue at the same time. This unique property is brief and starts with the fertilization of the ovum and ends when the embryo reaches the four to eight cells stage. Following that cells undergo subsequent divisions until reaching the blastocyst stage where they lose their totipotency property and assume a pluripotent identity where cells are only capable of differentiating into every embryonic germ layer (ectoderm, mesoderm and endoderm). Cells of this stage are termed embryonic stem cells and are obtained by isolation from the inner cell mass of the blastocyst in a process that involves the destruction of the forming embryo. After consecutive divisions, the property of pluripotency is lost and the differentiation capability becomes more lineage restricted where the cells become multipotent meaning that they can only differentiate into limited types of cells related to the tissue of origin. This is the property of adult stem cells, which helps create a state of homeostasis throughout the lifetime of the organism. Adult stem cells are present in a metabolically quiescent state in almost all specialized tissues of the body, which includes bone marrow and oral and dental tissues among many others (11).

Many authors consider adult stem cells the gold standard in stem cell-based therapies (12,13). Adult stem cells demonstrated signs of clinical success especially in hematopoietic transplants (14,15). In contrast to ESCs, adult stem cells are not subjected to controversial views regarding their origin. The fact that ESCs derivation involves destruction of human embryos renders them unacceptable for a significant proportion of the population for ethical and religious convictions (16-18).

It was in 2006 when Shinya Yamanka achieved a scientific breakthrough in stem cell research by succeeding in generating cells that have the same properties and genetic profile of ESCs. This was achieved via the transient over-expression of a cocktail of four transcription factors; OCT4, SOX2, KLF4 and MYC in, fully differentiated somatic cells, namely fibroblasts (19,20). These cells were called iPSCs and has transformed the field of stem cell research ever since (21). The most important feature of these cells is their ability to differentiate into any of the germ layers just like ESCs precluding the ethical debate surrounding their use. The development of iPSCs technology has created an innovative way to both identify and treat diseases. Since they can be generated from the patients own cells, iPSCs thus present a promising potential for the production of pluripotent derived patient-matched cells that could be used for autologous transplantation. True these cells symbolize a paradigm shift since they enable researchers to directly observe and treat relevant patient cells; nevertheless, a number of challenges still need to be addressed before iPSCs-derived cells can be applied in cell therapies. Such challenges include; the detection and removal of incompletely differentiated cells, addressing the genomic and epigenetic alterations in the generated cells and overcoming the tumorigenicity of these cells that could arise on transplantation (22).

With the rapid increase witnessed in stem cell basic research over the past years, the relatively new research discipline Translational Research has evolved significantly building up on the outcomes of basic research in order to develop new therapies. The clinical translation pathway starts after acquiring the suitable regulatory approvals. The importance of translational research lies in its a role as a filter to ensure that only safe and effective therapies reach the clinic (23). It bridges the gap from bench to bed. Currently, some stem cell-based therapies utilizing adult stem cells are clinically available and mainly include bone marrow transplants of hematopoietic stem cells and skin grafts for severe burns (23). To date, there are more than 3,000 trials involving the use of adult stem cells registered in WHO International Clinical Trials Registry. Additionally, initial trials involving the new and appealing iPSCs based therapies are also registered. In fact, the first clinical attempt employing iPSCs reported successful results in treating macular degeneration (24). Given the relative immaturity in the field of cellular therapy, the outcomes of such trials shall facilitate the understanding of the timeframes needed to achieve successful therapies and help in better understanding of the diseases. However, it is noteworthy that evaluation of stem cell-based therapies is not an easy task since transplantation of cells is ectopic and may result in tumor formation and other complications. This accounts for the variations in the results reported from previous reports. The following section discusses the published data of some of the most important clinical trials involving the use of different types of stem cells both in medicine and in dentistry.

The successful generation of neural cells from stem cells in vitro paved the way for the current stem cell-based clinical trials targeting neurodegenerative diseases (25,26). These therapies do not just target detaining the progression of irrecoverable neuro-degenerative diseases like Parkinsons, Alzheimers, amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS), but are also focused on completely treating such disorders.

PD is characterized by a rapid loss of midbrain dopaminergic neurons. The first attempt for using human ESC cells to treat PD was via the generation of dopaminergic-like neurons, later human iPSCs was proposed as an alternative to overcome ESCs controversies (27). Both cells presented hope for obtaining an endless source of dopaminergic neurons instead of the previously used fetal brain tissues. Subsequently, protocols that mimicked the development of dopaminergic neurons succeeded in generating dopaminergic neurons similar to that of the midbrain which were able to survive, integrate and functionally mature in animal models of PD preclinically (28). Based on the research presented by different groups; the Parkinsons Global Force was formed which aimed at guiding researchers to optimize their cell characterization and help promote the clinical progress toward successful therapy. Recently, In August 2018, Shinya Yamanka initiated the first approved clinical trial to treat PD using iPSCs. Seven patients suffering from moderate PD were recruited (29). Donor matched allogeneic cells were used to avoid any genetic influence of the disease. The strategy behind the trial involved the generation of dopaminergic progenitors followed by surgical transplantation into the brains of patients by a special device. In addition, immunosuppressant medications were given to avoid any adverse reaction. Preliminary results so far revealed the safety of the treatment.

MS is an inflammatory and neurodegenerative autoimmune disease of the central nervous system. Stem cell-based therapies are now exploring the possibility of halting the disease progression and reverse the neural damage. A registered phase 1 clinical trial was conducted by the company CelgeneTM in 2014 using placental-derived mesenchymal stem cells (MSCs) infusion to treat patients suffering from MS (30). This trial was performed at 6 centers in the United States and 2 centers in Canada and included 16 patients. Results demonstrated that cellular infusions were safe with no signs of paradoxical aggravation. However, clinical responses from patients indicated that the cellular treatment did not improve the MS condition (31). For the last decade immunoablative therapy demonstrated accumulative evidence of inducing long-term remission and improvement of disability caused by MS. This approach involves the replacement of the diseased immune system through administration of high-dose immunosuppressive therapy followed by hematopoietic stem cells infusion (32). However, immunoablation strategies demonstrated several complications such as infertility and neurological disabilities. A number of randomized controlled trials are planned to address these concerns (32). Currently, new and innovative stem cell-based therapies for MS are only in the initial stages, and are based on different mechanisms exploring the possibility of replacing damaged neuronal tissue with neural cells derived from iPSCs however, the therapeutic potential of iPSCs is still under research (33).

ALS is a neurodegenerative disease that causes degeneration of the motor neurons which results in disturbance in muscle performance. The first attempt to treat ALS was through the transplantation of MSCs in a mouse model. The outcomes of this experiment were promising and resulted in a decrease of the disease manifestations and thus providing proof of principal (34). Based on these results, several planned/ongoing clinical trials are on the way. These trials mainly assess the safety of the proposed concept and have not proved clinical success to date. Notably, while pre-clinical studies have reported that cells derived from un-diseased individuals are superior to cells from ALS patients; most of the clinical trials attempted have employed autologous transplantation. This information may account for the absence of therapeutic improvement reported (35).

Other neurologic indications for the use of stem cells are spinal cord injuries. Though the transplantation of different forms of neural stem cells and oligo-dendrocyte progenitors has led to growth in the axons in addition to neural connectivity which presents a possibility for repair (36), proof of recovered function has yet to be established in stringent clinical trials. Nevertheless, Japan has recently given approval to stem-cell treatment for spinal-cord injuries. This approval was based on clinical trials that are yet to be published and involves 13 patients, who are suffering from recent spinal-cord injury. The Japanese team discovered that injection of stem cells isolated from the patients bone marrow aided in regaining some lost sensation and mobility. This is the first stem cell-based therapy targeting spinal-cord injuries to gain governmental approval to offer to patients (37).

A huge number of the currently registered clinical trials for stem cell-based therapies target ocular diseases. This is mainly due to the fact that the eye is an immune privileged site. Most of these trials span various countries including Japan, China, Israel, Korea, UK, and USA and implement allogeneic ESC lines (35,36). Notably, the first clinical trial to implement the use autologous iPSCs-derived retinal cells was in Japan which followed the new regulatory laws issued in 2014 by Japans government to regulate regenerative medicine applications. Two patients were recruited in this trial, the first one received treatment for macular degeneration using iPSCs-generated retinal cell sheet (37). After 1 year of follow-up, there were no signs of serious complications including abnormal proliferation and systemic malignancy. Moreover, there were no signs of rejection of the transplanted retinal epithelial sheet in the second year follow-up. Most importantly, the signs of corrected visual acuity of the treated eye were reported. These results were enough to conclude that iPSCs-based autologous transplantation was safe and feasible (38). It is worthy to mention that the second patient was withdrawn from the study due to detectable genetic variations the patients iPSCs lines which was not originally present in the patients original fibroblasts. Such alterations may jeopardize the overall safety of the treatment. The fact that this decision was taken, even though the performed safety assays did not demonstrate tumorgenicity in the iPSCs-derived retinal pigment epithelium (RPE) cells, indicates that researchers in the field of iPSCs have full awareness of the importance of safety issues (39).

Pancreatic beta cells are destructed in type 1 diabetes mellitus, because of disorders in the immune system while in type 2 insulin insufficiency is caused by failure of the beta-cell to normally produce insulin. In both cases the affected cell is the beta cell, and since the pancreas does not efficiently regenerate islets from endogenous adult stem cells, other cell sources were tested (38). Pluripotent stem cells (PSCs) are considered the cells of choice for beta cell replacement strategies (39). Currently, there are a few industry-sponsored clinical trials that are registered targeting beta cell replacement using ESCs. These trials revolve around the engraftment of insulin-producing beta cells in an encapsulating device subcutaneously to protect the cells from autoimmunity in patients with type 1 diabetes (40). The company ViaCyteTM in California recently initiated a phase I/II trial ({"type":"clinical-trial","attrs":{"text":"NCT02239354","term_id":"NCT02239354"}}NCT02239354) in 2014 in collaboration with Harvard University. This trial involves 40 patients and employs two subcutaneous capsules of insulin producing beta cells generated from ESCs. The results shall be interesting due to the ease of monitoring and recovery of the transplanted cells. The preclinical studies preceding this trial demonstrated successful glycemic correction and the devices were successfully retrieved after 174 days and contained viable insulin-producing cells (41).

Stem cells have been successfully isolated from human teeth and were studied to test their ability to regenerate dental structures and periodontal tissues. MSCs were reported to be successfully isolated from dental tissues like dental pulp of permanent and deciduous teeth, periodontal ligament, apical papilla and dental follicle (42-44). These cells were described as an excellent cell source owing to their ease of accessibility, their ability to differentiate into osteoblasts and odontoblasts and lack of ethical controversies (45). Moreover, dental stem cells demonstrated superior abilities in immunomodulation properties either through cell to cell interaction or via a paracrine effect (46). Stem cells of non-dental origin were also suggested for dental tissue and bone regeneration. Different approaches were investigated for achieving dental and periodontal regeneration (47); however, assessments of stem cells after transplantation still require extensive studying. Clinical trials have only recently begun and their results are yet to be fully evaluated. However, by carefully applying the knowledge acquired from the extensive basic research in dental and periodontal regeneration, stem cell-based dental and periodontal regeneration may soon be a readily available treatment. To date, there are more than 6,000 clinical trials involving the use of with stem cells, however only a total of 44 registered clinical trials address oral diseases worldwide (48). Stem cell-based clinical trials with reported results targeting the treatment of oral disease are discussed below.

The first human clinical study using autologous dental pulp stem cells (DPSCs) for complete pulp regeneration was reported by Nakashima et al. in 2017 (49). This pilot study was based on extensive preclinical studies conducted by the same group (50). Patients with irreversible pulpitis were recruited and followed up for 6 months following DPSCs transplantation. Granulocyte colony-stimulating factor was administered to induce stem cell mobilization to enrich the stem cell populations. The research team reported that the use of DPSCs seeded on collagen scaffold in molars and premolars undergoing pulpectomy was safe. No adverse events or toxicity were demonstrated in the clinical and laboratory evaluations. Positive electric pulp testing was obtained after cell transplantation in all patients. Moreover, magnetic resonance imaging of the de-novo tissues formed in the root canal demonstrated similar results to normal pulp, which indicated successful pulp regeneration. A different group conducted a clinical trial that recruited patients diagnosed with necrotic pulp. Autologous stem cells from deciduous teeth were employed to induce pulp regeneration (51). Follow-up of the cases after a year from the intervention reported evidence of pulp regeneration with vascular supply and innervation. In addition, no signs of adverse effects were observed in patients receiving DPSCs transplantation. Both trials are proceeding with the next phases, however the results obtained are promising.

Aimetti et al. performed a study which included eleven patients suffering from chronic periodontitis and have one deep intra bony defect in addition to the presence of one vital tooth that needs extraction (52). Pulp tissue was passed through 50-m filters in presence of collagen sponge scaffold and was followed by transplantation in the bony defects caused by periodontal disease. Both clinical and radiographic evaluations confirmed the efficacy of this therapeutic intervention. Periodontal examination, attachment level, and probe depth showed improved results in addition to significant stability of the gingival margin. Moreover, radiographic analysis demonstrated bone regeneration.

The first clinical study using DPSCs for oro-maxillo-facial bone regeneration was conducted in 2009 (53). Patients in this study suffered from extreme bone loss following extraction of third molars. A bio-complex composed of DPSCs cultured on collagen sponge scaffolds was applied to the affected sites. Vertical repair of the damaged area with complete restoration of the periodontal tissue was demonstrated six months after the treatment. Three years later, the same group published a report evaluating the stability and quality of the regenerated bone after DPSCs transplantation (54). Histological and advanced holotomography demonstrated that newly formed bone was uniformly vascularized. However, it was of compact type, rather than a cancellous type which is usually the type of bone in this region.

Sjgrens syndrome (SS) is a systemic autoimmune disease marked by dry mouth and eyes. A novel therapeutic approach for SS. utilizing the infusion of MSCs in 24 patients was reported by Xu et al. in 2012 (55). The strategy behind this treatment was based on the immunologic regulatory functions of MSCs. Infused MSCs migrated toward the inflammatory sites in a stromal cell-derived factor-1-dependent manner. Results reported from this clinical trial demonstrated suppressed autoimmunity with subsequent restoration of salivary gland secretion in SS patients.

The ability to bank autologous stem cells at their most potent state for later use is an essential adjuvant to stem cell-based therapies. In order to be considered valid, any novel stem cell-based therapy should be as effective as the routine treatment. Thus, when appraising a type of stem cells for application in cellular therapies, issues like immune rejection must be avoided and at the same time large numbers of stem cells must be readily available before clinical implementation. iPSCs theoretically possess the ability to proliferate unlimitedly which pose them as an attractive source for use in cell-based therapies. Unlike, adult stem cells iPSCs ability to propagate does not decrease with time (22). Recently, California Institute for Regenerative Medicine (CIRM) has inaugurated an iPSCs repository to provide researchers with versatile iPSCs cell lines in order to accelerate stem cell treatments through studying genetic variation and disease modeling. Another important source for stem cells banking is the umbilical cord. Umbilical cord is immediately cryopreserved after birth; which permits stem cells to be successfully stored and ready for use in cell-based therapies for incurable diseases of a given individuals. However, stem cells of human exfoliated deciduous teeth (SHEDs) are more attractive as a source for stem cell banking. These cells have the capacity to differentiate into further cell types than the rest of the adult stem cells (56). Moreover, procedures involving the isolation and cryopreservation of these cells are un-complicated and not aggressive. The most important advantage of banking SHEDs is the insured autologous transplant which avoids the possibility of immune rejection (57). Contrary to cord blood stem cells, SHEDs have the ability to differentiate into connective tissues, neural and dental tissues (58) Finally, the ultimate goal of stem cell banking, is to establish a repository of high-quality stem cell lines derived from many individuals for future use in therapy.

With the increased number of clinical trials employing stem cells as therapeutic approaches, the need for developing regulatory guidelines and standards to ensure patients safety is becoming more and more essential. However, the fact that stem cell therapy is rather a new domain makes it subject to scientific, ethical and legal controversies that are yet to be regulated. Leading countries in the field have devised guidelines serving that purpose. Recently, the Food and Drug Administration (FDA) has released regulatory guidelines to ensure that these treatments are safe and effective (59). These guidelines state that; treatments involving stem cells that have been minimally manipulated and are intended for homogeneous use do not require premarket approval to come into action and shall only be subjected to regulatory guidelines against disease transmission. In 2014, a radical regulatory reform in Japan occurred with the passing of two new laws that permitted conditional approval of cell-based treatments following early phase clinical trials on the condition that clinical safety data are provided from at least ten patients. These laws allow skipping most of the traditional criteria of clinical trials in what was described as fast track approvals and treatments were classified according to risk (60). To date, the treatments that acquired conditional approval include those targeting; spinal-cord injury, cardiac disease and limb ischemia (61). Finally, regulatory authorities are now demanding application of standardization and safety regulations protocols for cellular products, which include the use of Xeno-free culture media, recombinant growth factors in addition to Good Manufacturing Practice (GMP) culture supplies.

Stem cell-based therapies face many obstacles that need to be urgently addressed. The most persistent concern is the ethical conflict regarding the use of ESCs. As previously mentioned, ESCs are far superior regarding their potency; however, their derivation requires destruction human embryos. True, the discovery of iPSCs overcame this concern; nevertheless, iPSCs themselves currently face another ethical controversy of their own which addresses their unlimited capacity of differentiation with concerns that these cells could one day be applied in human cloning. The use of iPSCs in therapy is still considered a high-risk treatment modality, since transplantation of these cells could induce tumor formation. Such challenge is currently addressed through developing optimized protocols to ensure their safety in addition to developing global clinical-grade iPSCs cell lines before these cells are available for clinical use (61). As for MSCs, these cells have been universally considered safe, however continuous monitoring and prolonged follow-up should be the focus of future research to avoid the possibility of tumor formation after treatments (62). Finally, it could be postulated that one of the most challenging ethical issues faced in the field of stem cell-based therapies at the moment, is the increasing number of clinics offering unproven stem cell-based treatments. Researchers are thus morally obligated to ensure that ethical considerations are not undermined in pursuit of progress in clinical translation.

Stem cell therapy is becoming a tangible reality by the day, thanks to the mounting research conducted over the past decade. With every research conducted the possibilities of stem cells applications increased in spite of the many challenges faced. Currently, progress in the field of stem cells is very promising with reports of clinical success in treating various diseases like; neurodegenerative diseases and macular degeneration progressing rapidly. iPSCs are conquering the field of stem cells research with endless possibilities of treating diseases using patients own cells. Regeneration of dental and periodontal tissues using MSCs has made its way to the clinic and soon enough will become a valid treatment. Although, challenges might seem daunting, stem cell research is advancing rapidly and cellular therapeutics is soon to be applicable. Fortunately, there are currently tremendous efforts exerted globally towards setting up regulatory guidelines and standards to ensure patients safety. In the near future, stem cell-based therapies shall significantly impact human health.

Ethical Statement: The author is accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

More:
Current state of stem cell-based therapies: an overview

1.Researchers Clarify the Identity of Stem Cells byUniversity of Calgary.Source:https://medicalxpress.com/news/2018-05-identity-brain-stem-cells.html

2.Bone Marrow Diseases byU.S. National Library of Medicine.Source:https://medlineplus.gov/bonemarrowdiseases.html

3.NCI Dictionary of Cancer Terms byNational Cancer Institute.Source:https://www.cancer.gov/publications/dictionaries/cancer-terms/def/blood-stem-cell

4.Muscle Stem Cells byNature.Source:https://www.nature.com/subjects/muscle-stem-cells

5.Stem Cells: Where Do They Live and What They Can Do? byEuroStemCell.Source:https://www.eurostemcell.org/skin-stem-cells-where-do-they-live-and-what-can-they-do

6.Liver Stem Cells byMatthews VB, Yeoh GC.Source:https://www.ncbi.nlm.nih.gov/pubmed/16118112

7.Regeneration in Humans byWikipedia.Source:https://en.wikipedia.org/wiki/Regeneration_in_humans#Naturally_regenerating_appendages_and_organs

8.Stem Cells in the Umbilical Cord byMark L. Weiss, Deryl L. Troyer.Source:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3753204/

9.Stem Cell Information byNational Institutes of Health.Source:https://stemcells.nih.gov/glossary.htm#ivf

10.Stem Cell Laws byWikipedia.Source:https://en.wikipedia.org/wiki/Stem_cell_laws#United_States

11.First Person Treated in Milestone Stem Cell Trial byAndy Coghlan.Source:https://www.newscientist.com/article/dn19570-first-person-treated-in-milestone-stem-cell-trial

12.Regulatory Considerations for Human Cells, Tissues, and Cellular and TissueBased Products: Minimal Manipulation and Homologous Use byFood and Drug Administration.Source:link

13.After Surgery: Discomforts and Complications byUniversity of Rochester.Source:https://www.urmc.rochester.edu/encyclopedia/content.aspx?ContentTypeID=85&ContentID=P01390

14.What proportion of patients report long-term pain after total hip or knee replacement for osteoarthritis? A systematic review of prospective studies in unselected patients byBeswick AD, Wylde V, Gooberman-Hill R, et al. Source:https://bmjopen.bmj.com/content/2/1/e000435

15.Many diseases increase the risks of hip fracture surgery byUniversity of Eastern Finland.Source:https://www.sciencedaily.com/releases/2018/11/181130111645.htm

16.Complications of total hip arthroplasty byGreg A Erens, MD. Source:https://www.uptodate.com/contents/complications-of-total-hip-arthroplasty

17.Reis RC, de Oliveira MF, Rotta JM, Botelho RV. Risk of complications in spine surgery: a prospective study. Open Orthop J. 2015;9:20-5. Published 2015 Jan 31. doi:10.2174/1874325001509010020. Source:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4321205/

18.Proietti L, Scaramuzzo L, Schiro GR, Sessa S, Logroscino CA. Complications in lumbar spine surgery: A retrospective analysis. Indian J Orthop. 2013;47(4):340-5. Source:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3745686/

19.Kroslak, M., & Murrell, G. A. C. (2018). Surgical Treatment of Lateral Epicondylitis: A Prospective, Randomized, Double-Blinded, Placebo-Controlled Clinical Trial. The American Journal of Sports Medicine, 46(5), 11061113. Source:https://journals.sagepub.com/doi/abs/10.1177/0363546517753385

20.Hackl M, Beyer F, Wegmann K, Leschinger T, Burkhart KJ, Mller LP. The treatment of simple elbow dislocation in adults. Dtsch Arztebl Int. 2015;112(18):311-9. Source:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4455254/

21.Backhouse MR, Vinall-Collier KA, Redmond AC, Helliwell PS, Keenan AM. Interpreting outcome following foot surgery in people with rheumatoid arthritis. J Foot Ankle Res. 2016;9:20. Published 2016 Jul 8. doi:10.1186/s13047-016-0153-6. Source:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4938997/

22.Chou LB, Wagner D, Witten DM, et al. Postoperative pain following foot and ankle surgery: a prospective study. Foot Ankle Int. 2008;29(11):1063-8. Source:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2743476/

23.Kise Nina Jullum, Risberg May Arna, Stensrud Silje, Ranstam Jonas, Engebretsen Lars, Roos Ewa M et al. Exercise therapy versus arthroscopic partial meniscectomy for degenerative meniscal tear in middle aged patients: randomised controlled trial with two year follow-up BMJ 2016; 354 :i3740. Source:https://www.bmj.com/content/354/bmj.i3740

24.Beaufils P, Becker R, Kopf S, Matthieu O, Pujol N. The knee meniscus: management of traumatic tears and degenerative lesions. EFORT Open Rev. 2017;2(5):195-203. Published 2017 May 11. doi:10.1302/2058-5241.2.160056. Source:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5489759/

25.New hip and knee replacements more likely to need repeat surgery byKate Devlin.Source:https://www.telegraph.co.uk/news/uknews/2663548/New-hip-and-knee-replacements-more-likely-to-need-repeat-surgery.html

26.Repeat hip and knee replacements cost $130 million annually byCanadian Institute for Health Information.Source:https://www.cihi.ca/en/repeat-hip-and-knee-replacements-cost-130-million-annually

27.Kain MS, Marcantonio AJ, Iorio R. Revision surgery occurs frequently after percutaneous fixation of stable femoral neck fractures in elderly patients. Clin Orthop Relat Res. 2014;472(12):4010-4. Source:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4397802/

28.Many young ACL surgery patients need second surgery later on byHospital for Special Surgery.Source:https://www.sciencedaily.com/releases/2015/05/150501103455.htm

29.Osteoarthritis and stem cell therapy in humans: a systematic review byJevotovsky DS, Alfonso AR, Einhorn TA, Chiu ES.Source:https://www.ncbi.nlm.nih.gov/pubmed/29544858

30.Cell-Based Therapies for Lumbar Discogenic Low Back Pain: Systematic Review and Single-Arm Meta-analysis. Wu T, Song HX, Dong Y, Li JH. Spine (Phila Pa 1976). 2018 Jan 1;43(1):49-57. doi: 10.1097/BRS.0000000000001549. Source:https://www.ncbi.nlm.nih.gov/pubmed/26953666

31.Fan X, Wang JZ, Lin XM, Zhang L. Stem cell transplantation for spinal cord injury: a meta-analysis of treatment effectiveness and safety. Neural Regen Res. 2017;12(5):815-825. Source:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5461621/

32.Lopes L, Setia O, Aurshina A, Liu S, Hu H, Isaji T, Liu H, Wang T, Ono S, Guo

X, Yatsula B, Guo J, Gu Y, Navarro T, Dardik A. Stem cell therapy for diabetic

foot ulcers: a review of preclinical and clinical research. Stem Cell Res Ther.

2018 Jul 11;9(1):188. doi: 10.1186/s13287-018-0938-6. PubMed PMID: 29996912;

PubMed Central PMCID: PMC6042254. Source:https://www.ncbi.nlm.nih.gov/pubmed/29996912

33.Hernigou P, Flouzat Lachaniette CH, Delambre J, Zilber S, Duffiet P,

Chevallier N, Rouard H. Biologic augmentation of rotator cuff repair with

mesenchymal stem cells during arthroscopy improves healing and prevents further

tears: a case-controlled study. Int Orthop. 2014 Sep;38(9):1811-8. doi:

10.1007/s00264-014-2391-1. Epub 2014 Jun 7. PubMed PMID: 24913770. Source:https://www.ncbi.nlm.nih.gov/pubmed/24913770

34.Rafael Nadal to undergo stem-cell treatments on his injured back byMatt Bonesteel.Source:https://www.washingtonpost.com/news/early-lead/wp/2014/11/10/rafael-nadal-to-undergo-stem-cell-treatments-on-his-injured-back/?utm_term=.c3e7dbd2f4c7

35.Pau Gasol has knee procedure, to receive stem cell injections byEric Pincus.Source:https://www.latimes.com/sports/lakers/lakersnow/la-sp-ln-lakers-pau-gasol-knee-procedure-20130509-story.html

36.Peyton Manning Underwent Stem Cell Treatment For Neck Injury byAmanda L. Chan.Source:https://www.huffpost.com/entry/peyton-manning-stem-cell-treatment_n_970763

37.Cristiano Ronaldo will undergo stem cell treatment as Real Madrid star races to be fit to face Manchester City in second-leg clash byOliver Todd.Source:https://www.dailymail.co.uk/sport/football/article-3562460/Cristiano-Ronaldo-undergo-stem-cell-treatment-Real-Madrid-star-races-fit-face-Manchester-City-second-leg-clash.html

38.What Is This Knee Treatment Kobe Bryant Goes All the Way to Germany For? byWill Carroll.Source:https://bleacherreport.com/articles/1798763-what-is-this-knee-treatment-kobe-bryant-goes-all-the-way-to-germany-for

39.PRP Therapy Helps Tiger Woods Recover byCedar Stem Cell Institute.Source:https://www.cedarsci.com/blog/prp-therapy-tiger-woods/

40.PRP, stem cell and Warriors G Steph Currys quick return from knee injury byJohn Canzano.Source:https://www.oregonlive.com/sports/oregonian/john_canzano/2016/04/steph_currys_return_from_mcl_s.html

41.STEM CELL THERAPY PLAYS A CRUCIAL ROLE FOR ATHLETES IN THE 2012 OLYMPIC GAMES: KOBE BRYANT, DARA TORRES AND DAVID PAYNE byMetro MD.Source:https://www.metro-md.com/stem-cell-therapy-plays-a-crucial-role-for-athletes-in-the-2012-olympic-games-kobe-bryant-dara-torres-and-david-payne/

42.Greens stem-cell success story bodes well for Manning byAlbert Breer.Source:http://www.nfl.com/news/story/09000d5d8227e0ce/article/greens-stemcell-success-story-bodes-well-for-manning

43.Mikirova NA, Casciari JJ, Hunninghake RE, Beezley MM. Effect of weight

reduction on cardiovascular risk factors and CD34-positive cells in circulation.

Int J Med Sci. 2011;8(6):445-52. Epub 2011 Aug 1. PubMed PMID: 21850193; PubMed

Central PMCID: PMC3156990. Source:https://www.ncbi.nlm.nih.gov/pubmed/21850193

44.Cerletti M, Jang YC, Finley LW, Haigis MC, Wagers AJ. Short-term calorie restriction enhances skeletal muscle stem cell function. Cell Stem Cell. 2012;10(5):515-9. Source:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3561899/

45.Mazzoccoli G, Tevy MF, Borghesan M, Delle Vergini MR, Vinciguerra M. Caloric

restriction and aging stem cells: the stick and the carrot? Exp Gerontol. 2014

Feb;50:137-48. doi: 10.1016/j.exger.2013.10.014. Epub 2013 Nov 6. Review. PubMed

PMID: 24211426. Source:https://www.ncbi.nlm.nih.gov/pubmed/24211426

46.The Okinawa diet could it help you live to 100? byMichael Booth.Source:https://www.theguardian.com/lifeandstyle/2013/jun/19/japanese-diet-live-to-100

47.Saki N, Jalalifar MA, Soleimani M, Hajizamani S, Rahim F. Adverse effect of high glucose concentration on stem cell therapy. Int J Hematol Oncol Stem Cell Res. 2013;7(3):34-40. Source:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3913149/

48.Ceccarelli G, Benedetti L, Arcari ML, Carubbi C, Galli D. Muscle Stem Cell and Physical Activity: What Point is the Debate at?. Open Med (Wars). 2017;12:144-156. Published 2017 Jul 24. doi:10.1515/med-2017-0022. Source:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5529938/

49.Mbius-Winkler S, Hilberg T, Menzel K, Golla E, Burman A, Schuler G, Adams V.

Time-dependent mobilization of circulating progenitor cells during strenuous

exercise in healthy individuals. J Appl Physiol (1985). 2009 Dec;107(6):1943-50.

doi: 10.1152/japplphysiol.00532.2009. Epub 2009 Oct 1. PubMed PMID: 19797690. Source:https://www.ncbi.nlm.nih.gov/pubmed/19797690

50.Schmidt A, Bierwirth S, Weber S, Platen P, Schinkthe T, Bloch W. Short

intensive exercise increases the migratory activity of mesenchymal stem cells. Br

J Sports Med. 2009 Mar;43(3):195-8. Epub 2007 Dec 10. PubMed PMID: 18070806. Source:https://www.ncbi.nlm.nih.gov/pubmed/18070806

51.Stories of Hope: A Stem Cell Therapy for Diabetes byCalifornias Stem Cell Agency.Source:https://www.cirm.ca.gov/our-progress/stories-hope-stem-cell-therapy-diabetes

52. Miana VV, Gonzlez EAP. Adipose tissue stem cells in regenerative medicine. Ecancermedicalscience. 2018;12:822. Published 2018 Mar 28. doi:10.3332/ecancer.2018.822. Source:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5880231/

53. FDA announces comprehensive regenerative medicine policy framework byFood and Drug Administration.Source:https://www.fda.gov/newsevents/newsroom/pressannouncements/ucm585345.htm

Read more here:
Stem Cell Therapy, Explained: Everything You Need To Know

"Stem cells have enormous potential for alleviating suffering for many diseases which currently have no effective therapy. The field has progressed to the clinic and it is important that this pathway is underpinned by excellent science and rigorous standards of clinical research. The journal provides an important avenue of publication in translational aspects of stem cell therapy spanning preclinical studies, clinical research and commercialization."

Timothy O'Brien,Editor-in-Chief,Stem Cell Research & Therapy

"The study of stem cells is one of the most exciting areas of contemporary biomedical research. We believe that Stem Cell Research & Therapy will act as a highly active forum for both basic and translational research into stem cell biology and therapies. Specifically, by developing this forum for cutting edge research, we hope that Stem Cell Research & Therapy will play a significant role in bringing together the critical information to synergize stem cell science with stem cell therapies."

Rocky S Tuan,Editor-in-Chief,Stem Cell Research & Therapy

Read this article:
Stem Cell Research & Therapy | Home page

Stem Cell Therapy for a Herniated Disc

A herniated disc is one of the major concerns of Modern Healthcare. Stem cell treatment for a herniated disc has opened new ways of non-surgical treatment of this syndrome by just an injection. The procedure involved injecting stem cells in the ruptured disc to stimulate the repair and provide relief from the extreme pain. The procedure has been fruitful in providing relief to people of all ages suffering from a herniated disc.

The stem cells injected into the patient body repairs herniated a disc and bring it back in shape. The body gets naturally repaired by this procedure and improves faster than any other surgical process.

There can be multiple reasons for a herniated disc. Regular wear and tear caused to the bone due to aging, heavy lifting and any traumatic events may be the cause of such issues.

The other reasons can be:

Overweight Too much of body weight can create extra pressure on the spine and lead to a herniated disc in the lower spinal region.

Extreme physical strain in work People engaged in particular occupations that include extreme physical stress or heavy lifting can cause discomfort in the back and cause a herniated disc. Pulling and pushing of heavy object in work also affect the back badly to rupture the disc.

Improper body posture Another important reason for a herniated disc is improper posters while standing or sitting.

Genetic Some people are genetically predisposed to be affected by a herniated disc.

Generally, a herniated disc occurs in the lumbar spine or the lower back. However, in some cases, it may occur in the cervical spine near the neck. The major symptoms of a herniated disc are as follows:

Limb pains Herniated disc cause in the limbs, thighs, buttocks, neck, shoulder, arms and calves. The pain pumps up while sneezing or coughing.

Numbness in certain body parts Herniated disc causes a tingling sensation, or sometimes numbness in various body parts as the nerves remain blocked. The same body parts also suffer from extreme pain in case treatment is delayed.

Weakness in muscles As the nerves get choked, the body muscles tend to lose strength. The body finds it difficult to perform strenuous works.

In rare cases, the body does not show any symptoms and are only diagnosed after imaging tests.

There are two steps of herniated disc treatment. Firstly the stem cells are collected from the patients bone marrow and in the second step are injected into the affected region. This cures and heals the ruptured disc as it gets more oxygen and improved immunity.

Bone marrow aspiration is done to collect stem cells. The hip is numbed to execute this procedure of inserting the needle to it and extract samples of bone marrow. Numbness in the hip makes it painless for the patients to go through the entire procedure.

The series is followed by a number of injections in the next 7 days to push back the stem cells to the body. The patient is sent for recovery after the stem cells are pushed back to her body. This can be a painful phase for patients for the first 3 to 4 weeks, but eventually, the pain gets off. Most patients have not a complaint of any pain after the procedure for more than 2 years.

The foremost benefit related to Stem Cell Therapy for a Herniated Disc is that the body gets to repair itself by its own. No external agent is pushed in the body for it to heal. The only thing it requires is the right execution of the procedure by qualified medical coordinators.

Also, this noninvasive procedure is popular due to its positive results in extreme cases of herniated discs. No artificial device is placed in the spine in this procedure and the disc ruptures are naturally cured.

The treatment for Stem Cell Therapy for a Herniated Disc is around $10, 000 on an average. The price depends on the experience of the medical practitioners executing the procedure, location and hospital facilities related to the recovery.

Stem Cell Therapy for a Herniated Disc costs much lower in Latin American countries like Mexico as medical expenses in this part of the world is way more affordable than any other places.

Like any other medical procedure, the success of Stem Cell Therapy for a Herniated Disc depends on the qualification and experience of the doctor performing it. It is very important to research the infrastructure and facilities of the hospital offering Stem Cell Therapy for a Herniated Disc before you register for it. Apart from this, it is equally important to know about the doctor who is performing this treatment for you. Once you have well research about these two things, you are one step ahead for a successful Stem Cell Therapy for a Herniated Disc treatment procedure.

If you are already suffering from a herniated disc and want to learn more about how stem cell therapy can work for you then use the button below:

See more here:
Stem Cell Therapy for a Herniated Disc - Global Stemcell ...

The stem cell procedure for the treatment of knee pain is minimally invasive, takes about 3 hours, and patients walk out of the office on their own following treatment. To start, stem cells are harvested from your abdominal or love handle fat using high tech, minimally-invasive liposuction equipment. Stem cells from your bone marrow are also utilized. The bone marrow concentrate is harvested using a specially designed, low-trauma needle which is placed into the posterior iliac crest under live x-ray guidance.

Mild IV sedation, in combination with local anesthetic, is used to provide patient comfort during the procedure. The harvested cells are then prepared for injection using an advanced separation and centrifugation process.

With the use of live x-ray guidance, the cells and growth factors are injected into the affected knee joint under sterile conditions. Dr. Brandts extensive experience with knee injections, along with the aid of the appropriate image guidance, ensures the cells are reaching their targeted area so you have the best chance for improvement.

To complement the high stem cell count achieved with the use of adipose derived stem cells, we often utilize PRP, A2M, and placental derived growth factors during our knee procedures and follow-up treatments.

Go here to see the original:
Stem Cell Therapy for Knees: Definitive Guide [with ...

Q: What are the types of stem cell therapy?

A: Stem cells are primitive cells that are capable of self-renewal (i.e., to divide to replenish their population); are pluripotent (i.e., able to differentiate into different mature cells); and are able to create, maintain, or repair tissues. There are several general categories of stem cells, including:

Two general stem-cell-based therapeutic strategies have been considered in MS:1

This document addresses AHSCT and MSC transplantation separately.

A: AHSCT is a multi-step procedure, which includes:

Mobilization typically is performed as an outpatient. Conditioning, PBHSC infusion, and initial recovery usually are performed during an approximately 1-month hospitalization in a specialized transplant unit.

A: A sizable number of case series, uncontrolled phase 2 clinical trials, and randomized clinical trials have demonstrated, in aggregate, potent efficacy of AHSCT in patients with active relapsing MS, including marked reduction in relapses, MRI lesion activity, and brain volume loss (after initial acceleration).1-3 In two analyses, the rate of no evidence of disease activity at 2 years was 70-90% in AHSCT case series and trials compared to 15-50% in clinical trials of MS disease modifying therapies (DMTs).4,5 A sizable proportion of patients treated with AHSCT demonstrate improvement in disability, for example, 64% at 4 years in a recent case series.6 Disease control often is durable, lasting up to 15 years or more without the need for ongoing disease modifying therapy (DMT) in many patients.7 Nonetheless, some patients require resumption of standard DMTs at some point after AHSCT, particularly with lower intensity non-myeloablative conditioning regimens.

The potent efficacy is attributed to immunoablative conditioning that depletes pathogenic immune cells; the durability of benefit is attributed more normal regulatory function and T-cell and B-cell repertoires following immune reconstitution.4

A: Early toxicity is common in patients undergoing AHSCT and potentially includes MS relapse during mobilization and conditioning, complications of leukapheresis, side effects of cytotoxic agents comprising the conditioning regimen (e.g., nausea or infertility), complications of myelosupression (e.g., infection or bleeding complications), and engraftment syndrome after re-infusion of PBHSCs (fever, rash, pulmonary edema, liver or renal impairment, and encephalopathy). Patients typically are hospitalized for approximately 1 month when undergoing conditioning and transplantation, and for initial recovery. Previous estimates of overall transplant-related mortality in MS were 2% or more. The current estimate is 0.2-0.3% for AHSCT performed after 2012.4 The improved safety is due to increased experience with the procedure, refinement of the protocol, and better selection of patients with lower risk of complications.

After recovery, adverse effects are rare and include infection (principally related to herpes zoster) and secondary autoimmune disorders. One potential advantage is that after AHSCT patients typically do not need ongoing MS DMT, with the associated cumulative risk of adverse effects.

A: The estimated cost for uncomplicated AHSCT is approximately $150,000. One potential advantage is that after recovery patients typically do not need ongoing MS DMT, with the associated cumulative cost. Nevertheless, most health insurance plans do not cover AHSCT, so obtaining coverage often is difficult.

A: Patients most likely to benefit from AHSCT are young (approximately 55 years or less), with relatively recent disease onset (approximately 10 years or less), still ambulatory, with highly active MS with recent clinical relapses or MRI lesion activity, and continued disease activity despite treatment with approved DMTs especially high-efficacy DMTs. Both the American Society for Blood and Marrow Transplantation 2 and National MS Society3 have published policy statements that AHSCT is a reasonable option in such patients, who are at high risk for disability.

A: Because of the complexity of the AHSCT procedure and the need for appropriate patient selection and follow-up, AHSCT for MS should be performed by centers with expertise and experience in transplant and that are affiliated with centers with experience and expertise in management of MS.1-3We advise patient not to undergo AHSCT in free-standing transplant clinics, especially in the absence of a detailed plan for follow-up and management of medical and neurologic issues post-transplant.

A: Because of the uncertain efficacy and safety of AHSCT compared to approved DMTs for MS, the Mellen Center is participating in the ongoing Best Available Therapy Versus Autologous Hematopoietic Stem Cell Transplant for Multiple Sclerosis (BEAT-MS) clinical trial sponsored by the National Institute of Allergy and Infectious Diseases and the Immune Tolerance Network (ClinicalTrials.gov Identifier: NCT04047628). This multicenter, randomized, rater-blinded trial compares the efficacy, safety, cost-effectiveness, and immunologic effects of AHSCT versus high-efficacy DMTs in participants with highly active, treatment-refractory, relapsing MS.

Because of unanswered questions regarding the efficacy of AHSCT in MS and substantial associated risk, our priority is to enroll patients for whom AHSCT is being considered into the BEAT-MS trial. We will consider AHSCT outside of the BEAT-MS trial for selected patients for whom AHSCT appears indicated but who are not eligible to participate in the study.

A: Typically, transplant physicians monitor and manage transplant-related adverse effects for the first 6 months following uncomplicated AHSCT (longer if there are complications). After 6 months following uncomplicated AHSCT, transplant-related adverse effects are rare. Patients need to be monitored primarily for symptoms or other findings suggesting infection or secondary autoimmune disorders. Long-term MS disease monitoring is similar to typical MS, with clinical visits and periodic MRIs.

A: Several analyses demonstrated that AHSCT has modest or no efficacy in preventing or reversing progressive disability worsening in the absence of recent relapses or MRI lesion activity. Conversely, the risk of adverse effects and transplant-related mortality are increased in progressive MS due to greater neurologic disability, older age, and increased likelihood of comorbidities. Many of the transplant-related deaths in recent series were patients with progressive MS.4 As a result, AHSCT generally is not advised for patients with non-active progressive MS and/or severe disability.

A: A recent publication reported potent efficacy of non-myeloablative AHSCT in preventing relapses, improving disability, and improving quality of life in 11 patients with aquaporin-4-positive neuromyelitis optica spectrum disorders (NMOSD).8 There now are 3 medications with regulatory approval to treat NMOSD plus several other medications used off-label. The findings from this small uncontrolled case series suggests AHSCT might be an option for patients with NMOSD who do not achieve adequate disease control from the available medication options. Rigorous formal clinical trials are needed to more definitively assess the efficacy and safety of AHSCT in NMOSD. We have not performed AHSCT for NMOSD at Cleveland Clinic.

A: Studies of various stem cell approaches to directly replace myelin-forming cells have been proposed (e.g., transplantation of oligodendrocyte progenitor cells or induced pluripotent stem cells), but none has been completed.1 To date, the most experience is with transplantation of mesenchymal stem cells (MSCs), pluripotent stromal cells present in a perivascular niche in a variety of tissues. In addition to their ability to differentiate into mesodermal lineage derivatives (e.g., bone, cartilage, connective tissue, and adipose tissue), MSCs appear to function to limit inflammatory tissue damage and promote tissue repair, including in the central nervous system, through elaboration of a large number of soluble immunomodulatory and trophic factors. These properties have led to a large number of studies investigating the potential benefit of MSC transplantation to treat a wide variety of inflammatory and tissue injury conditions.1 There also are a large number of commercial stem cell clinics offering MSC transplantation for a wide range of conditions.

A: A sizable number of preliminary trials of MSC transplantation in MS have been reported,1 including one conducted at the Mellen Center.9 These studies had different study populations, cell products, routes of administration, and study protocols, making it difficult to generalize the results. In aggregate, the studies reported good safety and tolerability, and some provided preliminary evidence of benefit. A recent study utilizing cell production procedures intended to augment production of neurotrophic factors by the MSCs and multiple intrathecal administrations, reported more prominent efficacy.10

Despite the sizable number of studies of MSC transplantation, there are a many unanswered technical questions, including the best tissue source (e.g., bone marrow, adipose tissue, or placenta/umbilical cord), whether the cells should be autologous (i.e., from the patient) or allogeneic (i.e., from someone without MS), the optimal cell culture methods to maximize yield and stimulate characteristics that increase therapeutic potency, whether the cells can be cryopreserved (frozen and stored) or need to be harvested directly from culture, dose (i.e., how many MSCs are administered), dosing schedule (i.e., for how long the therapeutic benefit lasts and how often the MSCs need to be administered), and optimal route of administration (i.e., intravenous, intrathecal, or both), among other issues. Because of these unanswered technical questions, MSC transplantation currently is an experimental treatment and should not be performed outside of rigorous formal clinical trials

A: There are a large number of commercial stem cell clinics in the U.S. and other countries offering treatments marketed as stem cells and presumed to be predominantly MSCs, on a fee-for service basis. However, because of the lack of quality control, lack of regulatory oversight, and lack of any validation of their efficacy or safety, we strongly advise patients not to pursue stem cell treatments at commercial stem cell clinics, outside of rigorous formal clinical trials. Many of these operations are potentially fraudulent.

Although MSC transplantation generally has been well-tolerated and safe in formal clinical trials, complications have been reported when administered in commercial stem cell clinics, including among other reports severe loss of vision following intravitreal injection11 and malignant spinal cord neoplasm following intrathecal injection.12

In addition, a number of concerns regarding commercial stem cell clinics have been raised: 13,14

A: Patient who undergo MSC transplantation should be monitored for symptoms or other findings indicating potential complications, including local or systemic infection, ectopic tissue formation, neoplasia, and arachnoiditis (following intrathecal administration). Long-term MS disease monitoring is similar to typical MS, with clinical visits and periodic MRIs.

Last Updated: 10 DEC 2020

Approach last updated: February 14, 2021

Read more:
Stem Cell Therapy | Mellon Center Approach | Cleveland Clinic

Sukoyan MA, Vatolin SY, et al. Embryonic stem cells derived from morulae, inner cell mass, and blastocysts of mink: comparisons of their pluripotencies. Embryo Dev. 1993;36(2):14858

Larijani B, Esfahani EN, Amini P, Nikbin B, Alimoghaddam K, Amiri S, Malekzadeh R, Yazdi NM, Ghodsi M, Dowlati Y, Sahraian MA, Ghavamzadeh A. Stem cell therapy in treatment of different diseases. Acta Medica Iranica. 2012:7996 https://www.ncbi.nlm.nih.gov/pubmed/22359076.

Sullivan S, Stacey GN, Akazawa C, et al. Quality guidelines for clinical-grade human induced pluripotent stem cell lines. Regenerative Med. 2018; https://doi.org/10.2217/rme-2018-0095.

Amps K, Andrews PW, et al. Screening ethnically diverse human embryonic stem cells identifies a chromosome 20 minimal amplicon conferring growth advantage. Nat. Biotechnol. 2011;29(12):112144.

Google Scholar

Amit M, Itskovitz-Eldor J. Atlas of human pluripotent stem cells: derivation and culturing. New York: Humana Press; 2012.

Google Scholar

Ludwig TE, Bergendahl V, Levenstein ME, Yu J, Probasco MD, Thomson JA. Feeder-independent culture of human embryonic stem cells. Nat Methods. 2006;3:63746.

CAS PubMed Google Scholar

Kang MI. Transitional CpG methylation between promoters and retroelements of tissue-specific genes during human mesenchymal cell differentiation. J. Cell Biochem. 2007;102:22439.

CAS PubMed Google Scholar

Vaes B, Craeye D, Pinxteren J. Quality control during manufacture of a stem cell therapeutic. BioProcess Int. 2012;10:505.

Bloushtain-Qimron N. Epigenetic patterns of embryonic and adult stem cells. Cell Cycle. 2009;8:80917.

CAS PubMed Google Scholar

Brindley DA. Peak serum: implications of serum supply for cell therapy manufacturing. Regenerative Medicine. 2012;7:80917.

Google Scholar

Solter D, Knowles BB. Immunosurgery of mouse blastocyst. Proc Natl Acad Sci U S A. 1975;72:5099102.

CAS PubMed PubMed Central Google Scholar

Hoepfl G, Gassmann M, Desbaillets I. Differentiating embryonic stem cells into embryoid bodies. Methods Mole Biol. 2004;254:7998 https://doi.org/10.1385/1-59259-741-6:079.

Google Scholar

Lim WF, Inoue-Yokoo T, Tan KS, Lai MI, Sugiyama D. Hematopoietic cell differentiation from embryonic and induced pluripotent stem cells. Stem Cell Res Ther. 2013;4(3):71. https://doi.org/10.1186/scrt222.

CAS Article PubMed PubMed Central Google Scholar

Mohr JC, de Pablo JJ, Palecek SP. 3-D microwell culture of human embryonic stem cells. Biomaterials. 2006;27(36):603242. https://doi.org/10.1016/j.biomaterials.2006.07.012.

CAS Article PubMed Google Scholar

Doetschman TC, Eistetter H, Katz M, Schmidt W, Kemler R. The in vitro development of blastocyst-derived embryonic stem cell lines: formation of the visceral yolk sac, blood islands, and myocardium. J Embryol Exp Morphol. 1985;87:2745.

CAS PubMed Google Scholar

Kurosawa HY. Methods for inducing embryoid body formation: in vitro differentiation system of embryonic stem cells. J Biosci Bioeng. 2007;103:38998.

Heins N, Englund MC, Sjoblom C, Dahl U, Tonning A, Bergh C, Lindahl A, Hanson C, Semb H. Derivation, characterization, and differentiation of human embryonic stem cells. Stem Cells. 2004;22:36776.

Rosowski KA, Mertz AF, Norcross S, Dufresne ER, Horsley V. Edges of human embryonic stem cell colonies display distinct mechanical properties and differentiation potential. Sci Rep. 2015;5:Article number:14218.

PubMed Google Scholar

Chung Y, Klimanskaya I, Becker S, Li T, Maserati M, Lu SJ, Zdravkovic T, Ilic D, Genbacev O, Fisher S, Krtolica A, Lanza R. Human embryonic stem cell lines generated without embryo destruction. Cell Stem Cell. 2008;2:1137.

CAS PubMed Google Scholar

Zhang X, Stojkovic P, Przyborski S, Cooke M, Armstrong L, Lako M, Stojkovic M. Derivation of human embryonic stem cells from developing and arrested embryos. Stem Cells. 2006;24:266976.

CAS PubMed Google Scholar

Beers J, Gulbranson DR, George N, Siniscalchi LI, Jones J, Thomson JA, Chen G. Passaging and colony expansion of human pluripotent stem cells by enzyme-free dissociation in chemically defined culture conditions. Nat Protoc. 2012;7:202940.

CAS PubMed PubMed Central Google Scholar

Ellerstrm C, Hyllner J, Strehl R. single cell enzymatic dissociation of human embryonic stem cells: a straightforward, robust, and standardized culture method. In: Turksen K, editor. Human embryonic stem cell protocols. Methods in molecular biology: Humana Press; 2009. p. 584.

Heng BC, Liu H, Ge Z, Cao T. Mechanical dissociation of human embryonic stem cell colonies by manual scraping after collagenase treatment is much more detrimental to cellular viability than is trypsinization with gentle pipetting. Biotechnol Appl Biochem. 2010;47(1):337.

Google Scholar

Ellerstrom C, Strehl R, Noaksson K, Hyllner J, Semb H. Facilitated expansion of human embryonic stem cells by single-cell enzymatic dissociation. Stem Cells. 2007;25:16906.

PubMed Google Scholar

Brimble SN, Zeng X, Weiler DA, Luo Y, Liu Y, Lyons IG, Freed WJ, Robins AJ, Rao MS, Schulz TC. Karyotypic stability, genotyping, differentiation, feeder-free maintenance, and gene expression sampling in three human embryonic stem cell lines deri. Stem Cells Dev. 2004;13:58597.

CAS PubMed Google Scholar

Watanabe K, Ueno M, Kamiya D, Nishiyama A, Matsumura M, Wataya T, Takahashi JB, Nishikawa S, Nishikawa S, Muguruma K, Sasai Y. A ROCK inhibitor permits survival of dissociated human embryonic stem cells. Nat Biotechnol. 2007;25:6816.

CAS PubMed Google Scholar

Nie Y, Walsh P, Clarke DL, Rowley JA, Fellner T. Scalable passaging of adherent human pluripotent stem cells. 2014. https://doi.org/10.1371/journal.pone.0088012.

Thomson JA, Itskovitz-Eldor J, Shapiro SS, Waknitz MA, Swiergiel JJ, Marshall VS, Jones JM. Embryonic stem cell lines derived from human blastocysts. Science. 1998;282:11457.

CAS PubMed Google Scholar

Martin MJ, Muotri A, Gage F, Varki A. Human embryonic stem cellsexpress an immunogenic nonhuman sialic acid. Nat. Med. 2005;11:22832.

CAS PubMed Google Scholar

Smith AG, Heath JK, Donaldson DD, Wong GG, Moreau J, Stahl M, Rogers D. Inhibition of pluripotential embryonic stem cell differentiation by purified polypeptides. Nature. 1988;336(6200):68890. https://doi.org/10.1038/336688a0.

CAS Article PubMed Google Scholar

Xu C, Inokuma MS, Denham J, Golds K, Kundu P, Gold JD, Carpenter MK. Feeder-free growth of undifferentiated human embryonic stem cells. Nature Biotechnol. 2001;19:9714. https://doi.org/10.1038/nbt1001-971.

CAS Article Google Scholar

Weathersbee PS, Pool TB, Ord T. Synthetic serum substitute (SSS): a globulin-enriched protein supplement for human embryo culture. J. Assist Reprod Genet. 1995;12:35460.

CAS PubMed Google Scholar

Chen G, Gulbranson DR, Hou Z, Bolin JM, Ruotti V, Probasco MD, Smuga-Otto K, Howden SE, Diol NR, Propson NE, Wagner R, Lee GO, Antosiewicz-Bourget J, Teng JM, Thomson JA. Chemically defined conditions for human iPSC derivation and culture. Nat. Methods. 2011;8:4249.

CAS PubMed PubMed Central Google Scholar

Sommer CA, Mostoslavsky G. Experimental approaches for the generation of induced pluripotent stem cells. Stem Cell Res Ther. 2010;1:26.

PubMed PubMed Central Google Scholar

Takahashi K, Yamanaka S. Induced pluripotent stem cells in medicine and biology. Development. 2013;140(12):245761 https://doi.org/10.1242/dev.092551.

CAS PubMed Google Scholar

Shi D, Lu F, Wei Y, et al. Buffalos (Bubalus bubalis) cloned by nuclear transfer of somatic cells. Biol. Reprod. 2007;77:28591. https://doi.org/10.1095/biolreprod.107.060210.

CAS Article PubMed Google Scholar

Gurdon JB. The developmental capacity of nuclei taken from intestinal epithelium cells of feeding tadpoles. Development. 1962;10:62240 http://dev.biologists.org/content/10/4/622.

CAS Google Scholar

Kain K. The birth of cloning: an interview with John Gurdon. Dis Model Mech. 2009;2(12):910. https://doi.org/10.1242/dmm.002014.

Article PubMed Central Google Scholar

Davis RL, Weintraub H, Lassar AB. Expression of a single transfected cDNA converts fibroblasts to myoblasts. Cell. 1987;24(51(6)):9871000.

Google Scholar

Quinlan AR, Boland MJ, Leibowitz ML, et al. Genome sequencing of mouse induced pluripotent stem cells reveals retroelement stability and infrequent DNA rearrangement during reprogramming. Cell Stem Cell. 2011;9(4):36673.

CAS PubMed PubMed Central Google Scholar

Maherali N, Sridharan R, Xie W, Utika LJ, Eminli S, Arnold K, Stadtfeld M, Yachechko R, Tchieu J, Jaenisch R, Plath K, Hochedlinger K. Directly reprogrammed fibroblasts show global epigenetic remodeling and widespread tissue contribution. Cell Stem Cell. 2007;1:5570.

CAS PubMed Google Scholar

Ohi Y, Qin H, Hong C, Blouin L, Polo JM, Guo T, Qi Z, Downey SL, Manos PD, Rossi DJ, Yu J, Hebrok M, Hochedlinger K, Costello JF, Song JS, Ramalho-Santos M. Incomplete DNA methylation underlines a transcriptional memory of somatic cells in human IPS cells. Nat Cell Biol. 2011;13:5419.

CAS PubMed PubMed Central Google Scholar

Zhou Q, Brown J, Kanarek A, Rajagopal J, Melton DA. In vivo reprogramming of adult pancreatic exocrine cells to beta-cells. Nature. 2008;455:62732 https://doi.org/10.1038/nature07314.

CAS PubMed Google Scholar

Hilfiker A, Kasper C, Hass R, Haverich A. Mesenchymal stem cells and progenitor cells in connective tissue engineering and regenerative medicine: is there a future for transplantation? Langenbecks Arch Surg. 2011;396:48997.

PubMed Google Scholar

Zhang Wendy, Y., de Almeida Patricia, E., and Wu Joseph, C. Teratoma formation: a tool for monitoring pluripotency in stem cell research. StemBook, ed. The Stem Cell Research Community. June 12, 2012. https://doi.org/10.3824/stembook.1.53.1.

Narsinh KH, Sun N, Sanchez-Freire V, et al. Single cell transcriptional profiling reveals heterogeneity of human induced pluripotent stem cells. J Clin Invest. 2011;121(3):121721.

CAS PubMed PubMed Central Google Scholar

Gertow K, Przyborski S, Loring JF, Auerbach JM, Epifano O, Otonkoski T, Damjanov I, AhrlundRichter L. Isolation of human embryonic stem cell-derived teratomas for the assessment of pluripotency. Curr Protoc Stem Cell Biol. 2007, Chapter 1, Unit 1B 4. 3: 1B.4.1-1B.4.29.

Cooke MJ, Stojkovic M, Przyborski SA. Growth of teratomas derived from human pluripotent stem cells is influenced by the graft site. Stem Cells Dev. 2006;15(2):2549.

CAS PubMed Google Scholar

Przyborski SA. Differentiation of human embryonic stem cells after transplantation in immune-deficient mice. Stem Cells. 2005;23:124250.

PubMed Google Scholar

Tannenbaum SE, Turetsky TT, Singer O, Aizenman E, Kirshberg S, Ilouz N, Gil Y, Berman-Zaken Y, Perlman TS, Geva N, Levy O, Arbell D, Simon A, Ben-Meir A, Shufaro Y, Laufer N, Reubinoff BE. Derivation of xeno-free and GMP-grade human embryonic stem cells- platforms for future clinical applications. PLoS One. 2012;7:e35325.

CAS PubMed PubMed Central Google Scholar

Cohen DE, Melton D. Turning straw into gold: directing cell fate for regenerative medicine. Nat Rev Genet. 2011;12:24352.

CAS PubMed Google Scholar

Hwang NS, Varghese S, Elisseeff J. Controlled differentiation of stem cells. Adv Drug Deliv Rev. 2007;60(2):199214. https://doi.org/10.1016/j.addr.2007.08.036.

CAS Article PubMed PubMed Central Google Scholar

Turner N, Grose R. Fibroblast growth factor signalling: from development to cancer. Nat Rev Cancer. 2010;10:11629.

CAS PubMed Google Scholar

Rao TP, Kuhl M. An updated overview on Wnt signaling pathways: a prelude for more. Circ Res. 2010;106:1798806.

CAS PubMed Google Scholar

Moustakas A, Heldin CH. The regulation of TGFbeta signal transduction. Development. 2009;136:3699714.

CAS PubMed Google Scholar

Excerpt from:
Stem cells: past, present, and future | Stem Cell Research ...

Stem cell therapy can help heart failure (HF) patients decrease their risk of a non-fatal myocardial infarction (MI) or stroke, according to new research presented at the American Heart Associations Scientific Sessions 2021.

Researchers tracked data from 537 patients with heart failure withreduced ejection fraction (HFrEF).Eighty percent of the patients were men, and the median age was 63 years old.

Patients were split into two groups: 261 patients were injected with 150 million mesenchymal precursor cells [stem cells] provided by healthy donors directly into the heart using a catheter, and 276 patients underwent a fake procedure.

According to the authors, patients were discharged from the hospital the day after the procedure and were followed for an average of 30 months.

Overall, the team associated stem cell use with a 65% decrease in non-fatal MIs and stroke events. Also,patients with high levels of inflammation (CRP levels of at least 2 mg/L) were 79% less likely to have non-fatal MI or stroke after being given stem cells.

Moreover, stem cell treatment lowered cardiac death by 80% in patients with high levels of inflammation and less severe HF.

However, the team added, there was no reduction in hospitalizations for HF among patients who received stem cells.

Cell therapy has the potential to change how we treat HF, lead author Emerson C. Perin, MD, PhD, director of the Center for Clinical Research and medical director of the Texas Heart Institute in Houston, said in a prepared statement. This study addresses the inflammatory aspects of HF, which go mostly untreated, despite significant pharmaceutical and device therapy development. Our findings indicate stem cell therapy may be considered for use in addition to standard guideline therapies.

See the rest here:
Stem cell therapy for heart failure lowers risk of adverse outcomes - Cardiovascular Business

Daniel Wiznia, MD, an orthopaedic surgeon with Yale School of Medicine, is practicing a surgical technique designed to render 10% of hip replacements unnecessary. Regenerative properties from a patients own stem cells are responsible for regrowing bone, restoring blood flow, and being able to avoid further interventional surgery.

Osteonecrosis, also known as avascular necrosis, occurs in more than 20,000 Americans each year. As the condition progresses, bone cells known as osteoblasts become unable to repair themselves and sustain the integrity of the bone, and ultimately die. The bone deterioration leads to a decrease in blood flow to the area, further weakening the entire skeletal structure of the upper leg. If unaddressed, the ball portion of the hips ball and socket joint will cave in on itself and collapse, requiring a total hip replacement.

The fact that patients often receive this diagnosis during their 30s and 40s presents a particular challenge. While the lifespan of hip prosthetics has dramatically increased in recent years, a patient who undergoes a total hip arthroplasty, or total hip replacement, at that age will almost certainly require a revision later in life. This redo of the same surgery at an older age comes with an entirely new set of risks and potential complications, making it that much harder to manage down the road.

The goal in patients with this condition then becomes very clear: prevent the head of the femur (thighbone) from collapsing.

Wiznia, assistant professor of orthopaedics and rehabilitation, and of mechanical engineering and materials science, draws from both of those areas of expertise to use 3D imaging technology as part of an innovative joint-preservation procedure. In recent years, he has worked closely with the Yale School of Engineering & Applied Sciences and the Integrated 3D Surgical Team at the Yale School of Medicine to tailor this treatment to each patient. Imaging has proven to be critical to the successful outcome of this surgical technique.

One of the challenges of orthopaedic surgery in the human body is that surgeons are operating in a three-dimensional space and are often reliant on two-dimensional imagery such as X-rays, Wiznia says. Through computer modeling, we are able to customize those images and create models that are specific to each patient, which, in turn, enhances outcomes and overall post-operative success rates.

Wiznia surgically harvests bone marrow from the patients pelvis. By using a centrifuge inside the operating room, he is able to isolate and concentrate the individuals own stem cells. Material containing the stem cells is then injected into the area of bone that has died.

Research has shown that stem cells possess the characteristics and qualities needed for the body to regrow, repair, and regenerate damaged tissue and bone, and according to Wiznia, this treatment dramatically reduces the risk of the head of the femur from collapsing. Soon after the procedure, many patients with avascular necrosis experience rejuvenated blood supply to the area and the bone is repopulated with new cells. This can additionally alleviate the short-term need for a hip replacement.

The major challenge in this patient population is identifying, diagnosing, and performing surgical intervention in time before the collapse. Because the vascular injury is usually a painless event, says Wiznia, patients are generally unaware of the specific point in time when the injury occurred, which is why cases are rarely discovered in time.

Patients may be encouraged to know that those who have avascular necrosis of the hip generally have it present on both sides, and it can develop on the two sides at different rates. So, even if it is detected too late on one side, there is still a chance to preserve the other.

We usually are able to catch that second asymptomatic side in those situations and conduct the core decompression with stem cell treatment before it collapses, Wiznia says. This novel stem cell therapy has demonstrated improved pain and function, and the stem cells decrease the risk of the femoral head from collapsing. That ultimately translates into fewer young patients requiring hip replacements along with subsequent surgeries in their later years.

Read this article:
Stem Cell Therapy Reduces Need for Nearly 10% of Hip Replacements - Yale School of Medicine