Category Archives: Stem Cells

Mutations in the gene that encodes a receptor called CCR5 can stop HIV (blue) entering immune cells.Credit: NIAID/National Institutes of Health/SPL

A 60-year-old man in Germany has become at least the seventh person with HIV to be announced free of the virus after receiving a stem-cell transplant1. But the man, who has been virus-free for close to six years, is only the second person to receive stem cells that are not resistant to the virus.

I am quite surprised that it worked, says Ravindra Gupta, a microbiologist at the University of Cambridge, UK, who led a team that treated one of the other people who is now free of HIV2,3. Its a big deal.

The first person found to be HIV free after a bone-marrow transplant to treat blood cancer4 was Timothy Ray Brown, who is known as the Berlin patient. Brown and a handful of others received special donor stem cells2,3. These carried a mutation in the gene that encodes a receptor called CCR5, which is used by most HIV virus strains to enter immune cells. To many scientists, these cases suggested that CCR5 was the best target for an HIV cure.

The latest case presented at the 25th International AIDS Conference in Munich, Germany, this week turns that on its head. The patient, referred to as the next Berlin patient, received stem cells from a donor who only had one copy of the mutated gene, which means their cells do express CCR5, but at lower levels than usual.

The case sends a clear message that finding a cure for HIV is not all about CCR5, says infectious-disease physician Sharon Lewin, who heads The Peter Doherty Institute for Infection and Immunity in Melbourne, Australia.

Ultimately, the findings widen the donor pool for stem-cell transplants, a risky procedure offered to people with leukaemia but unlikely to be rolled out for most individuals with HIV. Roughly 1% of people of European descent carry mutations in both copies of the CCR5 gene, but some 10% of people with such ancestry have one mutated copy5.

The case broadens the horizon of what might be possible for treating HIV, says Sara Weibel, a physician-scientist who studies HIV at the University of California, San Diego. Some 40 million people are living with HIV globally.

The next Berlin patient was diagnosed with HIV in 2009. He developed a type of blood and bone-marrow cancer known as acute myeloid leukaemia in 2015. His doctors could not find a matching stem-cell donor who had mutations in both copies of the CCR5 gene. But they found a female donor who had one mutated copy, similar to the patient. The next Berlin patient received the stem-cell transplant in 2015.

The cancer treatment went very well, says Christian Gaebler, a physician-scientist and immunologist at the Charit Berlin University Medicine, who presented the work. Within a month, the patients bone-marrow stem cells had been replaced with the donors. The patient stopped taking antiretroviral drugs, which suppress HIV, in 2018. And now, almost six years later, researchers cant find evidence of HIV replicating in the patient.

Previous attempts to transplant stem cells from donors with regular CCR5 genes have seen the virus reappear weeks to months after the people with HIV stopped taking antiretroviral therapy, in all but one person6. In 2023, Asier Sez-Cirin, an HIV researcher at the Pasteur Institute in Paris, presented data on an individual called the Geneva patient, who had been without antiretroviral therapy for 18 months7. Sez-Cirin says the person remains free of the virus, about 32 months later.

Researchers are now trying to work out why these two transplants succeeded when others have failed.

They propose several mechanisms. First, antiretroviral treatment causes the amount of virus in the body to drop considerably. And chemotherapy before the stem-cell transplant kills many of the hosts immune cells, which is where residual HIV lurks. Transplanted donor cells might then mark leftover host cells as foreign and destroy them, together with any virus residing in them. The rapid and complete replacement of the hosts bone-marrow stem cells with those of the donors might also contribute to the swift eradication. If you can shrink the reservoir enough, you can cure people, says Lewin.

The fact that both the next Berlin patient and his stem cell donor had one CCR5 gene copy with a mutation could have created an extra barrier to the virus entering cells, says Gaebler.

The case also has implications for therapies currently in early-stage clinical trials, in which the CCR5 receptor is sliced out of a persons own cells using CRISPRCas9 and other gene-editing techniques, says Lewin. Even if these therapies dont get to every single cell, they could still have an impact, she says.

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Seventh patient cured of HIV: why scientists are excited - Nature.com

Buitrago-Delgado, E., Nordin, K., Rao, A., Geary, L. & LaBonne, C. Shared regulatory programs suggest retention of blastula-stage potential in neural crest cells. Science 348, 13321335 (2015).

Article CAS PubMed PubMed Central Google Scholar

Le Douarin, N. & Kalcheim, C. The Neural Crest 2nd edn (Cambridge Univ. Press, 1999).

Schock, E. N., York, J. R. & LaBonne, C. The developmental and evolutionary origins of cellular pluripotency in the vertebrate neural crest.Semin. Cell Dev. Biol. 138, 3644 (2023).

Article CAS PubMed Google Scholar

York, J. R. & McCauley, D. W. The origin and evolution of vertebrate neural crest cells. Open Biol. 10, 190285 (2020).

Article CAS PubMed PubMed Central Google Scholar

Green, S. A., Simes-Costa, M. & Bronner, M. Evolution of vertebrates as viewed from the crest. Nature 520, 474482 (2015).

Article CAS PubMed PubMed Central Google Scholar

Lignell, A., Kerosuo, L., Streichan, S. J., Cai, L. & Bronner, M. E. Identification of a neural crest stem cell niche by Spatial Genomic Analysis. Nat. Commun. 8, 1830 (2017).

Article PubMed PubMed Central Google Scholar

Nordin, K. & Labonne, C. Sox5 is a DNA-binding cofactor for BMP R-Smads that directs target specificity during patterning of the early ectoderm. Dev. Cell 31, 374382 (2014).

Article CAS PubMed PubMed Central Google Scholar

Scerbo, P. et al. Ventx factors function as Nanog-like guardians of developmental potential in Xenopus. PLoS ONE 7, e36855 (2012).

Article CAS PubMed PubMed Central Google Scholar

Scerbo, P. & Monsoro-Burq, A. H. The vertebrate-specific VENTX/NANOG gene empowers neural crest with ectomesenchyme potential. Sci. Adv. 6, eaaz1469 (2020).

Article CAS PubMed PubMed Central Google Scholar

Rao, A. & LaBonne, C. Histone deacetylase activity has an essential role in establishing and maintaining the vertebrate neural crest. Development 145, dev163386 (2018).

Article PubMed PubMed Central Google Scholar

Geary, L. & LaBonne, C. FGF mediated MAPK and PI3K/Akt signals make distinct contributions to pluripotency and the establishment of neural crest. eLife 7, e33845 (2018).

Article PubMed PubMed Central Google Scholar

Zalc, A. et al. Reactivation of the pluripotency program precedes formation of the cranial neural crest. Science 371, eabb4776 (2021).

Article CAS PubMed PubMed Central Google Scholar

Pajanoja, C. et al. Maintenance of pluripotency-like signature in the entire ectoderm leads to neural crest stem cell potential. Nat. Commun. 14, dev165941 (2023).

Article Google Scholar

Sauka-Spengler, T., Meulemans, D. M., Jones, M. & Bronner-Fraser, M. Ancient evolutionary origin of the neural crest gene regulatory network. Dev. Cell 13, 405420 (2007).

Article CAS PubMed Google Scholar

Martik, M. L. et al. Evolution of the new head by gradual acquisition of neural crest regulatory circuits. Nature 574, 675678 (2019).

Article CAS PubMed PubMed Central Google Scholar

Takeuchi, M., Takahashi, M., Okabe, M. & Aizawa, S. Germ layer patterning in bichir and lamprey: an insight into its evolution in vertebrates. Dev. Biol. 332, 90102 (2009).

Article CAS PubMed Google Scholar

Cattell, M. V., Garnett, A. T., Klymkowsky, M. W. & Medeiros, D. M. A maternally established SoxB1/SoxF axis is a conserved feature of chordate germ layer patterning. Evol. Dev. 14, 104115 (2012).

Article CAS PubMed Google Scholar

Hockman, D. et al. A genome-wide assessment of the ancestral neural crest gene regulatory network. Nat. Commun. 10, 4689 (2019).

Article PubMed PubMed Central Google Scholar

Shi, G. & Jin, Y. Role of Oct4 in maintaining and regaining stem cell pluripotency. Stem Cell Res. Ther. 1, 39 (2010).

Article CAS PubMed PubMed Central Google Scholar

Thomson, M. et al. Pluripotency factors in embryonic stem cells regulate differentiation into germ layers. Cell 145, 875889 (2011).

Article CAS PubMed PubMed Central Google Scholar

Radzisheuskaya, A. et al. A defined Oct4 level governs cell state transitions of pluripotency entry and differentiation into all embryonic lineages. Nat. Cell Biol. 15, 579590 (2013).

Article CAS PubMed PubMed Central Google Scholar

Kim, D.-K., Cha, Y., Ahn, H.-J., Kim, G. & Park, K.-S. Lefty1 and lefty2 control the balance between self-renewal and pluripotent differentiation of mouse embryonic stem cells. Stem Cells Dev. 23, 457466 (2014).

Article CAS PubMed Google Scholar

Tosic, J. et al. Eomes and Brachyury control pluripotency exit and germ-layer segregation by changing the chromatin state. Nat. Cell Biol. 21, 15181531 (2019).

Article CAS PubMed Google Scholar

Acampora, D., Di Giovannantonio, L. G. & Simeone, A. Otx2 is an intrinsic determinant of the embryonic stem cell state and is required for transition to a stable epiblast stem cell condition. Development 140, 4355 (2013).

Article CAS PubMed Google Scholar

Ivanova, N. et al. Dissecting self-renewal in stem cells with RNA interference. Nature 442, 533538 (2006).

Article CAS PubMed Google Scholar

Zhang, X., Zhang, J., Wang, T., Esteban, M. A. & Pei, D. Esrrb activates Oct4 transcription and sustains self-renewal and pluripotency in embryonic stem cells. J. Biol. Chem. 283, 3582535833 (2008).

Article CAS PubMed Google Scholar

Guo, G. & Smith, A. A genome-wide screen in EpiSCs identifies Nr5a nuclear receptors as potent inducers of ground state pluripotency. Development 137, 31853192 (2010).

Article CAS PubMed PubMed Central Google Scholar

Gassler, J. et al. Zygotic genome activation by the totipotency pioneer factor Nr5a2. Science 378, 13051315 (2022).

Article CAS PubMed Google Scholar

Blij, S., Parenti, A., Tabatabai-Yazdi, N. & Ralston, A. Cdx2 efficiently induces trophoblast stem-like cells in nave, but not primed, pluripotent stem cells. Stem Cells Dev. 24, 13521365 (2015).

Article CAS PubMed PubMed Central Google Scholar

Rousso, S. Z. et al. Negative autoregulation of Oct3/4 through Cdx1 promotes the onset of gastrulation. Dev. Dyn. 240, 796807 (2011).

Article CAS PubMed Google Scholar

Han, J. et al. Tbx3 improves the germ-line competency of induced pluripotent stem cells. Nature 463, 10961100 (2010).

Article CAS PubMed PubMed Central Google Scholar

Russell, R. et al. A dynamic role of TBX3 in the pluripotency circuitry. Stem Cell Rep. 5, 11551170 (2015).

Article CAS Google Scholar

Tanaka, Y., Patestos, N. P., Maekawa, T. & Ishii, S. B-myb is required for inner cell mass formation at an early stage of development. J. Biol. Chem. 274, 2806728070 (1999).

Article CAS PubMed Google Scholar

Fernandez-Tresguerres, B. et al. Evolution of the mammalian embryonic pluripotency gene regulatory network. Proc. Natl Acad. Sci. USA 107, 1995519960 (2010).

Article CAS PubMed PubMed Central Google Scholar

Tanaka, S., Kunath, T., Hadjantonakis, A.-K., Nagy, A. & Rossant, J. Promotion of trophoblast stem cell proliferation by FGF4. Science 282, 20722075 (1998).

Article CAS PubMed Google Scholar

Yamaji, M. et al. PRDM14 ensures naive pluripotency through dual regulation of signaling and epigenetic pathways in mouse embryonic stem cells. Cell Stem Cell 12, 368382 (2013).

Article CAS PubMed Google Scholar

Grabole, N. et al. Prdm14 promotes germline fate and naive pluripotency by repressing FGF signalling and DNA methylation. EMBO Rep. 14, 629637 (2013).

Article CAS PubMed PubMed Central Google Scholar

Buitrago-Delgado, E., Schock, E. N., Nordin, K. & LaBonne, C. A transition from SoxB1 to SoxE transcription factors is essential for progression from pluripotent blastula cells to neural crest cells. Dev. Biol. 444, 5061 (2018).

Article CAS PubMed PubMed Central Google Scholar

Monsoro-Burq, A.-H., Wang, E. & Harland, R. Msx1 and Pax3 cooperate to mediate FGF8 and WNT signals during Xenopus neural crest induction. Dev. Cell 8, 167178 (2005).

Article CAS PubMed Google Scholar

Li, B., Kuriyama, S., Moreno, M. & Mayor, R. The posteriorizing gene Gbx2 is a direct target of Wnt signalling and the earliest factor in neural crest induction. Development 136, 32673278 (2009).

Article CAS PubMed PubMed Central Google Scholar

LaBonne, C. & Bronner-Fraser, M. Neural crest induction in Xenopus: evidence for a two-signal model. Development 125, 24032414 (1998).

Article CAS PubMed Google Scholar

Lander, R. et al. Interactions between Twist and other core epithelialmesenchymal transition factors are controlled by GSK3-mediated phosphorylation. Nat. Commun. 4, 1542 (2013).

Article PubMed Google Scholar

Mancilla, A. & Mayor, R. Neural crest formation in Xenopus laevis: mechanisms of Xslug induction. Dev. Biol. 177, 580589 (1996).

Article CAS PubMed Google Scholar

Rogers, C. D., Saxena, A. & Bronner, M. E. Sip1 mediates an E-cadherin-to-N-cadherin switch during cranial neural crest EMT. J. Cell Biol. 203, 835847 (2013).

Article CAS PubMed PubMed Central Google Scholar

LaBonne, C. & Bronner-Fraser, M. Snail-related transcriptional repressors are required in Xenopus for both the induction of the neural crest and its subsequent migration. Dev. Biol. 221, 195205 (2000).

Article CAS PubMed Google Scholar

Square, T. A. et al. Evolution of the endothelin pathway drove neural crest cell diversification. Nature 585, 563568 (2020).

Article CAS PubMed Google Scholar

Haldin, C. E. & LaBonne, C. SoxE factors as multifunctional neural crest regulatory factors. Int. J. Biochem. Cell Biol. 42, 441444 (2010).

Article CAS PubMed Google Scholar

Tapia, N. et al. Reprogramming to pluripotency is an ancient trait of vertebrate Oct4 and Pou2 proteins. Nat. Commun. 3, 1279 (2012).

Article PubMed Google Scholar

Nichols, J. et al. Formation of pluripotent stem cells in the mammalian embryo depends on the POU transcription factor Oct4. Cell 95, 379391 (1998).

Article CAS PubMed Google Scholar

Niwa, H., Miyazaki, J. & Smith, A. G. Quantitative expression of Oct-3/4 defines differentiation, dedifferentiation or self-renewal of ES cells. Nat. Genet. 24, 372376 (2000).

Article CAS PubMed Google Scholar

Onichtchouk, D. Evolution and functions of Oct4 homologs in non-mammalian vertebrates. Biochim. Biophys. Acta 1859, 770779 (2016).

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Shared features of blastula and neural crest stem cells evolved at the base of vertebrates - Nature.com

Imagine finding out that your bone marrow or blood stem cells could save the life of someone who needed it even a complete stranger. Memorial Sloan Kettering Cancer Center (MSK) nurse Grace Yang, RN, received such a call in March 2024.

This is definitely something I was never expecting to happen to me, Yang says. But because I work in the Bone Marrow Transplant [BMT] Service, I knew the impact it could have on somebody elses life. It felt like a privilege to be able to help in a different way. Yang works as an office practice nurse for BMT and cellular therapy specialist Heather Landau, MD.

Stem cell and bone marrow donations can offer people with blood cancer and other blood diseases the best chance for a cure. There is an urgent need for more donors between the ages of 18 and 40, especially donors of non-European and mixed ancestry. Yang, who is of Asian ancestry, was 29 when she donated.

You may wonder how to donate, whether donating bone marrow or blood stem cells is painful, and whats involved in bone marrow and stem cell transplantation procedures. Heres what you need to know.

First, some background: Transplanting donor stem cells that form new blood cells in a patient is a lifesaving treatment for many people with blood cancers like leukemia and lymphoma,as well as some other blood diseases. Contrary to what many people might think, the cells used in the transplant are usually collected from the donors bloodstream. Only on rare occasions are the stem cells taken from the bone marrow.

These donor cells are needed because before receiving a transplant, patients are given chemotherapyand sometimes radiationto wipe out the cancer. These treatments also destroy the patients blood-making cells.So they need healthy blood stem cells to be infused into their body. This transplant procedure enables patients to grow new blood cells and recover from the treatment.

Every year, about 18,000 people in the United States are diagnosed with a life-threatening illness for which a stem cell transplant from a donor is the best treatment option. Unfortunately, only about 30% of those patients have a family member who is the best match. That means that about 12,000 people need to find an unrelated donor.

One way that donors are found is through NMDP, which maintains a registry for connecting unrelatedvolunteer donorswith patientsin need. Unfortunately, many people are reluctant to join this registrybecause they dont realize the process is easier than they think, nor do they fully appreciate the desperate need for donors.

Yang signed up for the NMDP registry through a community drive, before she even worked in the BMT field. More than a decade later, she learned she was a match with a patient. I encourage all the people around me to sign up, she says. They are shocked that its so easy.

Even if a patient has an adult sibling who is the right age to donate, there is only a 1 in 4 chance a sibling will be a perfect match.

Siblings and other family members are often a half match, and this can be a good option for many patients. But for some patients, the best way to maximize the chances of a successful transplant is to find a fully matched donor even one who is unrelated.

There are a lot of misconceptions about donating bone marrow and stem cells, especially that it is a burden or painful.

When Yang first told her parents that she had been matched to a patient in need, she found out that her father had also donated bone marrow to stranger more than 20 years ago. At that time, the process was more complicated. Because of his past experience, her father was a bit concerned about what she might go through, but she explained that thanks to advances in technology, the donation process is much easier than it used to be.

Here is a step-by-step guide:

Because studies have shown that patients receiving blood stem cells from younger donors have a better long-term survival rate, you must be between the ages of 18 and 40 to join the registry.

Joining the registry is simple. Go to http://www.bethematch.org to order a collection test kit that will be sent to your house. The website may also direct you to a local registration drive in your area. Once you get the kit, all you need to do is wipe a cotton swab on the inside of your cheek, seal it in a provided container, and mail it back.

You will be contacted if you are a full match or a partial match for a patient in need of a bone marrow or stem cell transplant. Congratulations! Your cells may be the best option to save that persons life.

Several additional steps will be needed to confirm that a transplant with your cells is likely to be successful. These include filling out a health questionnaire, having additional blood tests, and undergoing a physical examination.

If testing confirms that you are a suitable donor, your donation will be scheduled for a time that works for you and for the patients treatment schedule. Depending on where you live, you may need to travel to one of the specialized facilities that collects the stem cells from blood or bone marrow. If you need to travel, your expenses will be covered by NMDP.

Yang traveled to Chicago to make her donation, and the NMDP not only arranged her trip and paid for everything, but it also paid for her sister to travel with her so she didnt have to go alone.

Thanks to procedures developed over the past few decades, 90% of the time the stem cells needed for the transplant are taken from the blood, not the bone marrow. This process is much easier for donors because it does not require surgery.

With stemcell donation from the blood, there is little pain. It is very similar to donating blood platelets. The main difference is that for a few days ahead of time, donors need to receive an injection of a drug called filgrastim (Neupogen), which stimulates the bone marrow to produce extra blood-forming stem cells. Donors may experience some bone pain or a low-grade fever while taking filgrastim, but the side effects usually are not severe and go away after the donation process is complete.

Most people are able to give themselves injections of filgrastim at home, so they dont need to go to the doctor every day.

On the day of the donation, the donor is hooked up to what is called an apheresis machine. The blood is collected from one arm, sent through a machine that removes the stem cells, and then returned to the other arm. Other than the initial needle prick, it is not a painful experience.

The process takes several hours, during which donors often read or watch movies. It may be necessary for donors to return for a second day, depending on how many cells are retrieved.

For Yang, the donation took about 3 hours. We started in the morning, and I was done before lunch, she says. The nurses did a great job of making me feel comfortable and checked on me often throughout the process.

In only about 10% of cases, doctors may recommend the patient receive a bone marrow donation requiring a surgical procedure. Donors are placed under general anesthesia, while bone marrow is removed from small holes drilled into their pelvic bones.

This procedure takes an hour or two, and usually donors can go home that same day.

If you have donated stem cells from your blood, you may feel tired for a few days, but many donors feel no effects at all the next day.

If you have donated bone marrow, you will probably have some pelvic and hip pain, as well as some bruising, for a few days after the procedure. These aches and pains can be controlled with over-the-counter pain medications like Advil and Tylenol. Most people can go back to regular activities right away, but your medical team can provide more details for specific activities.

The process by which the donor and recipient are matched is called HLA (human leukocyte antigen) typing. Its not the same as blood type.Instead, it has to do with the immune proteins that we all inherit at birth from both of our parents. The immune system uses these proteins to understand which cells belong to your body and which do not. A perfect match means that 8 out of 8 markers are the same.

Matching is not related to gender, so your donation can go to someone of any gender as long as the HLA markers align.

Yang has not yet learned anything about the patient who received her cells, but hopes to in the coming months. I just feel so lucky that I was able to do something amazing for somebody else, she says.

Not everyone who needs a donor is able to find one who is fully matched. A patients best chance of finding a donor is someone within their own ethnic group. Members of certain ethnic groups, including those of Latin American, Asian, African, and Middle Eastern ancestry, have a harder time finding a match. These groups tend to be underrepresented in public registries.

For example, for people of Latin American descent, the odds of finding a matched donor in a public registry are less than 50%. For Black patients, the odds are only about 30%. It may be even harder for people of mixed ethnic backgrounds to find donors because their HLA makeup can be more complex.

This makes it especially important for people from these underrepresented ethnic groups, as well as those who have mixed ancestry, to join a public registry like NMDP.

For patients who are unable to find a fully matched donor, there are other options. These include:

These treatments can offer patients very good outcomes, but in some cases its better to have a donor who is a perfect match.

Yang says even though she works as a BMT nurse, she still had questions throughout the donation process. Everyone at NMDP is great about addressing any concerns you may have about the process, and they have many great resources, she says. Any time I have the opportunity to talk to someone about this, I encourage them to get involved.

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Donating Bone Marrow and Stem Cells: The Process and What To Expect - On Cancer - Memorial Sloan Kettering

A recent clinical study by Pipeleers and colleagues has brought the possibility of a stem-cell based cure one step closer1. This perspective will summarize the major hurdles that have been overcome to deliver cell-based improvements in glucose control and highlight the key issues that stand between this important proof-of-concept clinical study and a durable cure for the majority of patients living with T1D.

The autoimmune destruction of pancreatic cells creates a lifelong dependence on insulin to control blood sugar levels in individuals with type 1 diabetes (T1D). Over time, poorly managed T1D causes microvascular and macrovascular complications that significantly impact quality of life2. Unfortunately, intensive glucose lowering therapy to reduce these long-term complications of hyperglycemia is accompanied by an increased risk of hypoglycemic events3. Technological solutions aiming to replace cell function with an artificial pancreas can improve glucose control by integrating continuous glucose monitoring with automated insulin delivery4. However, these systems have not yet matched the exquisite blood glucose control provided by human islets5, and T1D patients remain burdened with the ongoing management and expense of a chronic disease.

Therapeutic approaches aimed at restoring a functional -cell mass could eventually eliminate the need for exogenous insulin. Indeed, transplant of cadaveric islets into immunosuppressed T1D recipients has shown that excellent glucose control can be achieved6, while simultaneously reducing hypoglycemic risk7. The benefits of islet transplant to individual T1D islet recipients should not be minimized, however, the limited supply of donor tissue constrains the potential impact of this strategy, which is still only available to clinical trial participants in many countries including the USA. In contrast, human pluripotent stem cells (hPSCs)8,9 could theoretically be expanded and differentiated to restore a functional -cell mass in all eligible patients with T1D if they can be shielded from autoimmune attack.

Initially, a major goal was to optimize stem cell differentiation protocols to produce glucose-responsive cells from hPSCs. The first major success was guided by developmental studies from diverse model organisms10, in which step-wise modulation of key developmental signals produced cells capable of expressing insulin11, albeit at low levels and in a largely constitutive manner. Nevertheless, this was a remarkable demonstration that hPSCs have the potential to be used for cell-replacement therapy. Extensive empirical optimization and an appreciation of the functional importance of islet structure led to -cells with improved function12,13. We note, the in vitro generation and characterization of stem-cell derived islets has been recently reviewed14. However, the observation that in vitro differentiated hPSC-derived -cells exhibit immature physiological responses15, like many other hPSC-derived cell products16, led to consideration of alternative strategies. A surprisingly effective approach has involved halting in vitro differentiation once pancreatic fate is established at the multipotent pancreatic progenitor (PP) stage and allowing -cell differentiation and functional maturation to be guided by endogenous cues post-transplant17. An added benefit of this approach is that PP differentiation is amenable to the large-scale expansion and Good Manufacturing Practice (GMP) production and quality control required for clinical application18. Interestingly, further differentiation and enrichment of hormone-positive islet-like cells prior to transplant does not reduce the in vivo maturation time19.

Now that a suitable cell-source is available, preventing graft rejection is one of the greatest challenges facing hPSC-based therapies. The autoimmune nature of T1D poses a challenge for cell-based therapies since the immune system is poised to destroy newly transplanted material, even if it is derived from the patients own stem cells. As seen with cadaveric transplants, systemic immunosuppression can protect and maintain unmatched donor cells in a functional state6. Furthermore, clinical transplants have shown that ~10,000 islet equivalents/kg provide a functional -cell mass that can eliminate the need for exogenous insulin20, setting a clear goal for therapeutic effect. Unfortunately, this blunt force approach trades dependence on insulin for continuous immunosuppression, which brings increased risks of infections, certain cancers and regimen-specific toxicities21.

Encapsulating transplants in biocompatible materials that prevent immune infiltration, while permitting sufficient diffusion of nutrients and waste products to support -cell health, has been pursued to eliminate the need for systemic immunosuppression. Despite the demonstration over 40 years ago that microencapsulation is sufficient to preserve islet function for several weeks in an animal model without immune suppression22, maintaining a functional -cell mass within cell-impermeable materials remains a major challenge. Microencapsulated islets (single islets or small clusters) can disperse into the recipient tissue where they benefit from a large contact area with the host. However, the impermeable barrier prevents direct contact with blood vessels, which produce a basement membrane that is likely essential for optimal -cell function23. These problems have been even more pronounced in cell-impermeable macroencapsulation devices, where elaborate designs such as intravascular hollow fibers are used to increase exposure to the bloodstream24. However, despite the theoretical advantages of close contact with the blood stream, the serious risk of blood clots associated with vascular prostheses has impeded clinical translation of intravascular devices25. The strengths and weaknesses of additional islet encapsulation technologies have been recently reviewed26.

Because cell impermeable materials necessarily prevent direct contact between -cells and the endothelium, some groups have gone a different direction with cell-permeable devices, including Viacyte with the VC-02 device. Although the exact configuration of the VC-02 remains proprietary, key features that appear to have contributed to clinical success are a perforated encapsulation membrane that is encased in another layer of perforated non-woven fabric27. The VC-02 device loaded with hPSC-derived Pancreatic Endoderm Cells (PECs) that are partially differentiated to the PP stage has been coined the PEC-Direct (Fig. 1).

Partially differentiated hPSC-derived PECs were loaded into devices that mature under the protection of systemic immunosuppression in T1D patients. The perforated design facilitates the infiltration of endothelial cells, while the external non-woven fabric restricts fibrotic foreign body responses. After maturation, functional cells comprised 3% of the total cell mass. MO macrophage, T T cell, NK Natural Killer cell.

While most clinical experience is associated with transplant of cadaveric islets to the portal vein in the liver, additional subcutaneous, omental, and intramuscular sites have been extensively studied in preclinical models28. These sites may pose additional challenges for islet survival since the limited clinical data available suggests that unencapsulated extrahepatic transplants do not perform well29. However, encapsulated hPSC-derived PPs transplanted subcutaneously differentiate into tissue that contains functional glucose responsive cells within 4-6 months in animal models30,31. Building on this experience, two parallel first-in-human studies aimed to optimize the cell dose and perforation configuration of PEC-Direct subcutaneous implants in small numbers of T1D recipients (n=1732; n=1533) demonstrated that C-peptide, a marker produced by insulin-secreting cells, could be newly detected in some individuals at 6 months post-transplant and could persist until 24 months. A subset of patients achieved >30 pM C-peptide after meal stimulation (6/24, note some individuals were analyzed in both studies), a level that is associated with reduced T1D complications34. However, none of the individuals reached the 200 pM threshold associated with improved metabolic control34 or the 1000 pM level associated with insulin independence in cadaveric islet recipients35. For reference, postprandial C-peptide levels range from 1000-3000 pM in healthy individuals36. Importantly, the observed insulin production could be directly attributed to the VC-02 devices, and not the recovery of the recipients own cell function, since removal of the explants eliminated the improvements in C-peptide levels in two patients where this was carefully explored33. While comparison of transplanted PEC cells with cadaveric islets in terms of islet equivalents can only be approximated, these pilots delivered at most one-half the transplant volume required for insulin independence. Since the recovered devices contained mostly glucagon+ cells (16%) and only a small fraction of insulin+ cells (3%) it is not surprising that the transplants were not sufficient to improve secondary measures of glycemia. Regardless, these first-in-human studies demonstrated the overall safety of the approach in high risk (hypoglycemia unaware) patients with all serious adverse events attributed to the immunosuppressive regimen or surgical procedure, suggesting that maximizing transplant size and -cell composition were going to be crucial for clinical impact.

In an interim report of 1-year outcomes, Keymeulen et al., now provide evidence that hPSC transplants are on the cusp of providing benefit to many patients. Using an adaptive trial design, the transplant volume was increased 2-3 fold and all devices used the perforation pattern and density associated with the best outcomes in previous trials32,33 The transplant recipients were selected using similar criteria to the previous trials, requiring stable T1D (>5 years), a high risk for hypoglycemic complications (Clarke score 4), and meal-stimulated C-peptide levels 30 pM prior to transplant. With the increased dose and optimized device configuration, 3/10 recipients produced 100 pM postprandial C-peptide from 6-months post-transplant and one surpassed the 200 pM threshold associated with metabolic significance. Excitingly, this individual achieved improved time spent in the target blood sugar range (by continuous glucose monitoring), a clinically meaningful measure of function.

Now that hPSC-derived cells have been shown to produce metabolically significant amounts of insulin in a T1D patient, there is a path to match and potentially exceed the outcomes observed with cadaveric transplants. Assuming a linear relationship between -cell mass and insulin secretion, it appears that a further ~10-fold increase in functional -cell mass would be sufficient to achieve insulin-independence (>1000 pM C-peptide) in some patients and a metabolic benefit (>200 pM C-peptide) in most recipients. Unfortunately, simply further increasing the transplant size would likely increase surgical complications. Consistent across the clinical trials, recovered PEC-Direct devices contained large acellular regions filled with extracellular matrix. This material permanently occupies space that could be better utilized as cells currently comprise at most ~3% of the total volume within a device1. Although histological analysis of the PEC-Direct devices retrieved from the non-responders was not available in the interim report, further insight into the fate of transplanted PPs and the composition of infiltrating cells in failed grafts will help focus future efforts. Interestingly, in samples from two responders, the less functional graft was already dominated by infiltrating recipient cells at 3 months post-transplant and the cell mass was negligible at 9 months despite having a larger total cell volume1. Human islets are composed of ~50% cells that are interspersed with other endocrine cell types and aligned to the vasculature37. Thus, if the majority of the device volume were filled with islet-like structures, there should be a sufficient functional cell mass for most patients.

Recapitulating embryonic pancreatic development in vitro has produced PPs that clearly have the potential to complete differentiation into functional cells in a process that takes 4-6 months post-transplant. Additional clues from developmental biology indicate that there are stage-specific interactions between endogenous endocrine precursors and the vasculature that influence pancreatic differentiation. Initially, endothelial cells induce the differentiation of endocrine cells38, which then signal back to increase the density of the local vascular network39 and deposition of a vascular basement membrane that promotes cell function23. Thus, cells participate in the construction of a specialized niche through interactions with the vasculature that are essential for subsequent cell maturation. While the perforated design of the PEC-Direct device allows infiltration of endothelial cells, the growth of this vascular network takes time and is competing with recipient fibroblasts which are only partially blocked by the outer non-woven fabric layer (Fig. 1), suggesting that there are limitations to mechanical control of these processes. The strengths and weaknesses of the PEC-Direct device compared to other cell-based therapies are summarized in Table 1. Here, we highlight recent advances that could help maximize the yield of vascularized cells and in the best-case scenario provide an immune privileged niche that would eliminate the need for systemic immunosuppression (Fig. 2).

Immunomodulatory materials and cells could be used to create an immune privileged niche for transplanted PECs and further discourage fibroblast infiltration. cell numbers could potentially be increased by improving the microenvironment and converting other pancreatic cell types to the cell fate. MO macrophage, T T cell, NK Natural Killer cell. Treg Regulatory T cell, M2 M2 macrophage, CXCL12 CXCL12 chemokine.

The materials in the PEC-Direct device, particularly the outermost non-woven fabric layer, suppress a full-blown foreign body response associated with the recruitment of macrophages and fibroblasts to the interface with recipient tissues27. Limiting residual fibroblast infiltration1 might be most important in the acute post-transplant period, as they likely interfere with PP differentiation and the establishment of the intra-device vascular network. The precise composition of the perforated VC-02 encapsulation membrane remains proprietary. However, if it is composed of alginate or similar material, then biomodulatory factors could be directly integrated into the encapsulation membrane40. Notably, incorporation of the CXCL12 chemokine was recently shown to protect microencapsulated xenogeneic islets in a non-human primate model41. The primary mechanism of acute islet protection is associated with repulsion of islet-reactive effector T cells42. However, CXCL12 has multiple immune modulatory roles43, and protected islets also show reduced macrophage and fibroblast surface infiltration and collagen deposition40,41. These studies suggest that incorporating chemokine(s) such as CXCL12 into the encapsulation membrane, or potentially adding an additional biomodulatory layer, could improve the microenvironment within the device. Additional advances in biomaterials functionalized with diverse immunomodulatory molecules have been recently reviewed in the context of islet transplantation44.

Giving the vasculature a head start could be a complementary way to limit the opportunities for intra-device fibrosis. Instead of relying exclusively on the recipients vasculature, the addition of ready-made microvessels isolated from adipose tissue to hPSC-derived PPs improved early graft survival and reduced the time required for cell differentiation to less than 10 weeks in mouse T1D models45. Harvesting recipient microvessels would add additional complexity to a clinical transplant program but a proof-concept pilot study using healthy donor microvessels could be informative. Ideally, microvessel-equivalents would also be produced from hPSCs46, although scale up under GMP conditions as was done for PPs18 would also be needed.

Improving the intradevice microenvironment might increase not only the mature pancreatic cell volume within a device but potentially also the proportion of cells. In the small number of recovered grafts that have been analyzed histologically, cells comprise at most ~3% of the total cell volume1,33,34. In contrast, preclinical studies with similar device-encapsulated PPs have produced grafts with up to 16% cells by transplanting into a preformed pouch at the surgical site47. Presumably, the 5 weeks between pouch formation and device engraftment allowed for vascularization of the transplant site and resolution of acute inflammatory responses. Importantly, these data indicate that partially differentiated PPs are capable of producing significantly more cells within an optimized microenvironment. Beyond improving the host environment, an attractive source of additional cells is from transdifferentiated cells, which are invariably the most abundant pancreatic cell type identified after in vivo maturation of PPs1,47. While paracrine signals from cells are important for optimal cell function48, these intraislet interactions are unlikely to be compromised by the transdifferentiation of excess cells that are currently produced in superphysiological proportions. Furthermore, reducing cell content in the graft could have metabolic benefits as there is growing evidence that hyperglucagonemia interferes with cell function49. cells have an innate ability to transdifferentiate, although it is only triggered by near complete cell destruction50,51. Overexpression of the key cell transcription factors PDX1 and MAFA in adult cells produces -like cells with the ability to sense glucose and secrete insulin52,53, although these cells retain aspects of their previous cell identity. To avoid perturbing differentiation to the PP stage in vitro, implementing directed transdifferentiation in hPSC-derived transplants will require engineered stem cells with the ability to induce cell factors specifically in mature endocrine cells54. A further 2-3 fold increase of the cell mass observed in preclinical studies via transdifferentiation would produce structures with very similar cellular composition to endogenous human islets37.

The ultimate goal of a hPSC-based therapy for T1D is to provide long-term cell function without the need for systemic immunosuppression. Cotransplantation of microgels containing individual immunomodulatory factors such as PD-L155 or FasL56 can have profound effects on graft survival in immunocompetent hosts. For example, FasL presenting microbeads combined with only two weeks of rapamycin monotherapy supported graft function for over six months and induced Treg-dependent local tolerance without systemic effects on the immune system in an allogeneic mouse model56. Similar effects were seen in non-human primates57, although the long-term viability of the grafts was not evaluated.

In addition to achieving allogeneic graft tolerance, hPSC-derived cells must contend with the dysregulated autoimmune response in T1D. Excitingly, it now appears possible to fully cloak hPSCs and their differentiated progeny by overexpressing a cocktail of 8 immunomodulatory factors that includes PD-L1 and FASL58. Together, these factors disrupt antigen presentation, T-cell and NK cell attack, and innate inflammatory responses. By activating a proliferation-dependent kill switch59, cloaked cells could be maintained in a dormant state within an immunocompetent host. Furthermore, these cloaked cells protected their neighbors, including allogeneic islets and xenogeneic hPSCs. While PPs could potentially be generated directly from cloaked hPSCs, the overexpression of 8 genes might impact cell function long-term. An elegant strategy to address all the key issues discussed here would be to generate cloaked endothelial cells for cotransplantation with PPs that are genetically primed for to cell transdifferentiation.

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Finishing the odyssey to a stem cell cure for type 1 diabetes - Nature.com

Marketing by some private biobanks may be misleading expectant parents about the procedures value, writes Jacklin Kwan

Umbilical cord blood banking has gained prominence in the past decade as an option for expectant parents worried about their childs future health.1 Parents pay private biobank companies up to 3000 (excluding annual storage fees) to freeze their babys cord blood, which contains stem cells, in case the infant develops a condition that could be treated with stem cell therapy.

Cells4Life, which claims to be the UKs largest private biobank for cord blood banking, says that its particular method delivers more stem cells from umbilical cord blood than its competitors processes. For this marketing message it relies on research published in the Journal of Stem Cells Research, Development & Therapy. Publication of this research took place just 17 days after receipt of the manuscript, a timescale far shorter than is typical for peer reviewed journals. Two editors listed on the journals editorial board say they did not in fact hold these roles, The BMJ discovered (box 1).

Cells4Life says it is the UKs largest provider of cord blood banking services. The firm markets its proprietary technology TotiCytea precise, low concentration mixture of two solutions, the cryoprotectants dimethyl sulfoxide (DMSO) and dextranas the reason why, after collection, processing, and freezing, its samples have three times as many stem cells as competitors that use other processing methods (assuming that freezing and collection are kept the same across all methods).

Patricia Murray, professor of stem cells and regenerative medicine at the University of Liverpool, says that there is no clear scientific reason why TotiCyte should outperform market alternatives. All theyve got in TotiCyte is DMSO and dextran, which are well established cryoprotectants, she said, There may just be a slight difference in the percentages of DMSO and dextran, but you wouldnt expect it to have such a dramatic effect on cell survival.

Responding to this, Cells4Lifes chief executive, Claudia Rees, says that TotiCyte is used as a blood separation reagent to sediment red blood cells so they can be removed before freezing, not as a cryoprotectant.

Murray points to a written opinion by an international searching authority (ISA or patent office) in 2014 when Cells4Life applied for a patent under the World Intellectual Property Organisation. The ISA examined TotiCytes application to sediment red blood cells as well as its role as a cryoprotectant and concluded: It follows that the addition of DMSO to the dextran composition does not add any technical effect in the use and method for white blood cell enrichment and appears merely to serve as a patent strategical means to establish novelty over the art.

Rees told The BMJ that Cells4Life has been granted patents in the US and China for TotiCyte as proof of its novelty.

The evidence for Cell4Lifes TotiCyte claim is given in a peer reviewed publication, the Journal of Stem Cells Research, Development & Therapy, published by Herald Scholarly Open Access. The research article referenced by Cells4Life was received on 14 May 2021 and published only 17 days later.2 When asked by The BMJ, the journal in question claims to maintain a double blind process of peer review.

However, a 2017 study of journal response times suggests that journals typically take 12-14 weeks to handle accepted medicine and public health papers.3 This is the time in which the paper is under the responsibility of the journalin other words, the time it takes for the journal to evaluate the manuscripts, find reviewers, have time for the reviewers to complete their work, and for editors to evaluate manuscripts on the basis of reviewers reports. It does not include the time taken for authors to revise and resubmit their work.

The BMJ contacted two editors who were listed on the journals editorial board. One said that they had never held an active role in the journal nor received any articles or communications from them for review or any other purpose. The other said that they never accepted the position of editor to this journal.

After being contacted by The BMJ, both researchers have asked the Journal of Stem Cells Research, Development & Therapy to remove their names. The BMJ was unable to make contact with the journal about this matter.

Rees says, The Journal of Stem Cells Research, Development & Therapy has its own independent editorial board, provides an NLM [National Library of Medicine] identifier [and] an impact factor, and operates under the COPE guidelines. COPE is the Committee of Publication Ethics, a non-profit organisation that promotes and defines best practices in scholarly publishing.

Experts in regenerative medicine have criticised Cell4Lifes marketing directed at expectant parents, which they say contains misleading statements. Charles Murry, director of the Institute for Stem Cell and Regenerative Medicine at the University of Washington, Seattle, says claims that stem cells can develop into almost any type of cell in the body have been very rigorously disproven.

Depending on the specific company and on whether parents choose also to bank cord tissue, private umbilical cord blood banking services range from 550 to around 3000, excluding annual storage fees of over 100 to keep samples frozen. Those financial costs are often marketed as an investment, given that there have been promising reports of successful use of stem cell based therapies to treat a wide range of potentially life threatening diseases, from cerebral palsy to leukaemia.45

The Cells4Life website claims that umbilical cord blood is routinely used in treatments for over 80 different conditions and diseases, including cancers, blood disorders, immune disorders, and autism. It says, Umbilical cord blood stem cells are pure and plastic, meaning that they can become almost any cell in the human body, and, They can become almost any tissue type in the body and may even be used to regrow entire organs.

But Murry says this list of applications is unrealistic. There were people making these claims in the late 1990sthat these cells have the plasticity to become other thingsbut thats been very rigorously disproven.678 He tells The BMJ that the haematopoietic stem cells (HSCs) and mesenchymal stem or stromal cells (MSCs) harvested from cord blood (box 2) are a form of adult stem cell and that there is a restricted repertoire of what theyre able to develop intonamely, blood cells for HSCs and connective tissue cells for MSCs.

Blood in the umbilical cord contains haematopoietic stem cells, which can be used to develop into different kinds of blood cells (such as red blood cells), and mesenchymal stem cells (stromal cells), which are important for repairing some body tissues. After birth, the umbilical cord can be clamped and the blood within it and the placenta cryogenically stored. According to the Human Tissue Authority, 376843 units of cord blood were stored with the UKs private cord blood biobanks at the end of 2022, representing over 90% of the countrys total stores of cord blood supply. The remainder is stored in philanthropic umbilical cord blood banks, such as the independent charity Anthony Nolan,9 to which parents can choose to donate cord blood for other patients or research.

Stem cell therapies are showing promise in treating some conditions that diminish quality of life, such as cerebral palsy.4 Finding a stem cell match through public banks or within families can be a challenge.

Responding to this criticism, Cells4Life says, Any cursory search of published literature on future applications of perinatal stem cells demonstrates the huge potential that cord blood holds for use in regenerative medicine in the future. It references papers in which MSCs are used to reduce inflammatory immune responses after organ transplantations and adds: MSCs can be transformed into inducible pluripotent stem cells (iPSCs). This technology allows a cell to mimic an embryonic stem cell capable of forming any tissue with [the] exception of germ cells.

But Murry considers the claims of pluripotency and the ability to develop into any tissue potentially misleading, because they do not give parents the whole picture. He says that transforming stem cells into iPSCs requires highly trained stem cell scientists to reprogramme the cell. The biobanks store the starting material in a 1000 step journey, he says, They dont provide you with a route to a scientist in a lab.

Also, you can make iPSCs from your blood or from your skin as an adult, Murry adds, meaning that cord blood banking is unnecessary for this process.

Many other private biobanks make similar claims about the therapeutic potential of cord blood. SmartCells, a competing cord blood bank, claims on its website: As the bodys building blocks, the possibilities for using stem cells are endless. These potent cells are unique because they have the ability to repair, replace, and regenerate cells of almost any kind.

Future Health Biobank, another private cord blood bank service, lists treatment possibilities on its website, naming over 75 genetic, immune, and blood disorders that can be treated with HSCs.

Pietro Merli is a paediatrician at the Bambino Ges paediatric hospital in Rome, Italy, where he uses HSCs and other cell products to treat his patients. He also believes that the lists of diseases and disorders claimed by the biobanks to be treatable with MSCs and HSCs are unrealistic.

He explains that many of the disorders and diseases he treats with HSCs do not require autologous stem cells, harvested from the patients, and can instead use allogeneic stem cells from donors who are HLA (human leucocyte antigen) matched to patients. There are many conditions that can be treated with haematopoietic stem cell transplants, but these are allogeneic stem cell transplants, not autologous, he says.

Merli says that the few instances in which doctors might use autologous HSC transplants are in treating lymphomas. But you can use your own stem cells from bone marrow, which are harvested during your treatment, he said, adding that there is no benefit to harvesting and storing stem cells from cord blood.

Merli says that in Italy, where he practises, such advertising by stem cell therapy companies is illegal. He also says that no cord blood bank he has seen details how patients would hypothetically be able to use their preserved stem cells.

Neither SmartCells nor Future Health responded to The BMJs request for comment.

The Royal College of Obstetricians and Gynaecologists and the Royal College of Midwives do not recommend commercially harvesting umbilical cord blood, unless theres a specific medical reason to do so.10

Murry says the decision whether to bank their infants cord blood ultimately lies with parents: If the cost is not a big deal for you, and it brings you peace of mind, go for it.

Competing interests: I have read and understood the BMJ Group policy on declaration of interests and have no relevant interests to declare.

Commissioning and peer review: Commissioned; externally peer reviewed.

This feature has been funded by the BMJ Investigations Unit. For details see bmj.com/investigations. Got a story? Contact us: investigations@bmj.com

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Cord blood banking: Experts raise concern over claims made for stem cell applications - The BMJ

Pregnant women are bombarded with advertisements on social media, in childbirth classes, even in their doctors offices urging them to bank the blood in their babys umbilical cord and gain peace of mind.

Private banks claim that the stem cells inside the blood are a powerful tool to have on hand in case a child one day becomes seriously ill. They charge several thousand dollars upfront for storage plus hundreds more every year thereafter.

But an investigation by The New York Times found that leading banks have consistently misled parents about the technologys promise. The few parents who try to withdraw samples often find that they are unusable either because their volume is too low or they have been contaminated with microbes.

Heres what parents should know about cord blood banking.

In the 1990s, transplant doctors saw cord blood as a promising new source of stem cells for patients with sickle cell anemia and leukemia who could not find suitable matches from their families or bone marrow donor registries.

The major cord blood banks Cord Blood Registry, ViaCord and Cryo-Cell told The Times that the cells they store had saved childrens lives and that no one knew what scientists may one day discover.

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What Parents Should Know About Cord Blood Banking - The New York Times

Marty FM, Ljungman P, Chemaly RF, Maertens J, Dadwal SS, Duarte R, et al. Letermovir prophylaxis for cytomegalovirus in hematopoietic-cell transplantation. N Engl J Med. 2017;377:243344.

Article CAS PubMed Google Scholar

Vyas A, Raval AD, Kamat S, LaPlante K, Tang Y, Chemaly RF. Real-world outcomes associated with letermovir use for cytomegalovirus primary prophylaxis in allogeneic hematopoietic cell transplant recipients: a systematic review and meta-analysis of observational studies. Open Forum Infect Dis. 2022;10:ofac687.

Article PubMed PubMed Central Google Scholar

Cassaniti I, Colombo AA, Bernasconi P, Malagola M, Russo D, Iori AP, et al. Positive HCMV DNAemia in stem cell recipients undergoing letermovir prophylaxis is expression of abortive infection. Am J Transplant. 2021;21:162228.

Article CAS PubMed Google Scholar

Solano C, Gimnez E, Albert E, Piana JL, Navarro D. Immunovirology of cytomegalovirus infection in allogeneic stem cell transplant recipients undergoing prophylaxis with letermovir: a narrative review. J Med Virol. 2023;95:e29005.

Article CAS PubMed Google Scholar

Gimnez E, Guerreiro M, Torres I, Aguilar C, Albert E, Hernndez-Boluda JC, et al. Features of cytomegalovirus DNAemia and virus-specific T-cell responses in allogeneic hematopoietic stem-cell transplant recipients during prophylaxis with letermovir. Transpl Infect Dis. 2023;25:e1402.

Article Google Scholar

Solano C, Gimnez E, Piana JL, Vinuesa V, Poujois S, Zaragoza S, et al. Preemptive antiviral therapy for CMV infection in allogeneic stem cell transplant recipients guided by the viral doubling time in the blood. Bone Marrow Transplant. 2016;51:71822.

Article CAS PubMed Google Scholar

Huntley D, Talaya A, Gimnez E, Martnez A, Hernndez-Boluda JC, Hernani R, et al. Features of cytomegalovirus DNAemia Blips in allogeneic hematopoietic stem cell transplant recipients: implications for optimization of preemptive antiviral therapy strategies. Biol Blood Marrow Transplant. 2020;26:9727.

Article CAS PubMed Google Scholar

Zamora D, Duke ER, Xie H, Edmison BC, Akoto B, Kiener R, et al. Cytomegalovirusspecific Tcell reconstitution following letermovir prophylaxis after hematopoietic cell transplantation. Blood. 2021;138:3443.

Article CAS PubMed PubMed Central Google Scholar

Gabanti E, Borsani O, Colombo AA, Zavaglio F, Binaschi L, Caldera D, et al. Human cytomegalovirusspecific Tcell reconstitution and lateonset cytomegalovirus infection in hematopoietic stem cell transplantation recipients following letermovir prophylaxis. Transplant Cell Therapy. 2022;28:211.e1211.e9.

Article CAS Google Scholar

Lauruschkat CD, Muchsin I, Rein A, Erhard F, Grathwohl D, Dlken L, et al. CD4+T cells are the major predictor of HCMV control in allogeneic stem cell transplant recipients on letermovir prophylaxis. Front Immunol. 2023;14:1148841.

Article CAS PubMed PubMed Central Google Scholar

Zavaglio F, Vitello D, Bergami F, Arena F, Borsani O, Colombo AA, et al. Human Cytomegalovirus (HCMV)-specific T-cell response after letermovir prophylaxis is predictive for subsequent HCMV reactivation in haematopoietic stem cell transplant recipients. J Clin Virol. 2023;165:105519.

Article CAS PubMed Google Scholar

Lauruschkat CD, Muchsin I, Rein AF, Erhard F, Grathwohl D, Dlken L, et al. Impaired T and memory-like NK-cell reconstitution is linked to late-onset HCMV reactivation after letermovir cessation. Blood Adv. 2024;8:296779.

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Assessment of Cytomegalovirus DNA doubling time and virus-specific T-cell responses in the management of CMV infection in allogeneic hematopoietic...

Chulalongkorn Universitys Faculty of Veterinary Science and the Faculty of Engineering have worked together to research and develop a three-dimensional artificial cornea from stem cells that offers a way to treat deep corneal wounds in dogs. The innovation helps to solve the problem of treatment methods that rely on tissue replacement which is hard to find and very expensive. It makes it possible for dogs to be able to see clearly and comfortably once again.

Does your dog have any of these symptoms? The inability to fully open its eyes, squinting or blinking frequently, shedding lots of tears, sometimes the tears are thick, and the mucus appears greenish. The sclera is unusually red and not clear like before. The cornea becomes cloudy and there are blood vessels in it.

If your answer is yes then your pet might be suffering from a corneal ulcer which, if left untreated could eventually cause blindness.

Nowadays, the number of dogs receiving treatment for corneal ulcers has increased tremendously.The small animal hospital at the Faculty of Veterinary Medicine, Chulalongkorn Universityalone is already treating dogs with corneal ulcers daily.

Veterinarian Dr. Chutirat Torssahakul,the Department of Internal Medicine, Faculty of Veterinary Medicine

We find quite a number of lesions like this in dogs. Corneal ulcers occur as a result of many reasons, such as dogs scratching their own eyes because they have allergies causing itching around the eyes followed by scratching until the lesions form. Fights with other dogs, being scratched by a cat, or accidentally bumps into objectsVeterinarian Dr. Chutirat Torssahakul of the Department of Internal Medicine,Faculty of Veterinary Medicine, Chulalongkorn Universityaddressed the problems that became the starting point for the research and innovation development. Three-dimensional artificial cornea from stem cells enables your beloved pet to have perfect vision once again. The current treatment being used is to have grafts made from replacement tissue derived from porcine bladder or canine placentas which are rare and relatively expensive. There is also the possibility of causing post-surgery reaction and inflammation. Therefore, we thought that if we could produce our own innovative artificial cornea using natural materials that are easily found and reduce the chance of causing inflammation this might be a better option. Dr. Chutirat explained.

Three-dimensional artificial cornea from stem cells a brighter alternative

As a result of the effort and intention to solve eye problems for dogs, the Faculty of Veterinary Sciences research team throughthe Veterinary Stem Cell and Bioengineering Innovation Center (VSCBIC)has therefore embarked on additional studies on stem cells and is working with the Biomedical Engineering Research Center of the Faculty of Engineering, Chulalongkorn University recognizing its expertise in tissue engineering to help make adhesive materials for growing stem cells.

Image showing a 3D corneal patch made from silk fibroin and gelatin

According to Veterinary Professor Dr. Chutirat Artificial corneal tissue is obtained by cultivating real dog corneal stem cells on a natural material structure made from silk fibroin mixed with gelatin. The material can be cheaply and easily found in Thailand. It is strong and durable, clear and transparent, and adheres well to cells making them three-dimensional which is comparable to real corneal tissue.

This innovation can be used to treat corneal perforations in dogs as well as large corneal wounds where the tissue cannot be stitched or even deep wounds in which a large amount of corneal tissue has been lost. In cases of dogs with mild or moderate levels of corneal ulcer problems, currently, 2 methods for treatment are still in use.

But in cases where the wound in the cornea is so large that tissue must be used to replace the missing part, we usually use a graft which could be the dogs own conjunctiva. The other option is to use replacement tissue such as tissues derived from human or canine placentas. These are costly and difficult to find so we have invented a new way to treat them and that is the three-dimensional artificial cornea made from stem cells.

4 outstanding features of the 3D artificial cornea innovation

At present, the 3D artificial cornea from stem cells innovation is still in the laboratory testing stage to study whether the 3D artificial cornea can actually be used as a cornea replacement, and to determine how it interacts with the animals body. According to Veterinary Professor Dr. Chutirat in many countries research on such innovations is also currently underway at the laboratory level.

The research we have done has produced satisfactory results. It is expected that this innovation will be applied to dogs in the next few years. Moreover, we have plans to apply this knowledge to cats as well from cell collection, locating cells, separating cells, and arranging cells Dr. Chutirat concluded.

Those who are interested can further read the research paper on the subject at https://pubmed.ncbi.nlm.nih.gov/35120168/

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3D Artificial Cornea from Stem Cells: Chula Researchers Advance Canine Corneal Wound Treatment - Times Higher Education

NEW YORK, July 20, 2024 (GLOBE NEWSWIRE) -- Cell BioEngines, Inc., a New York, USA-based company researching stem cells in order to develop new cell therapies unlocked $1.75 million additional funds from SOSV and the Partnership Fund through the new therapeutics seed track, available for therapeutics start-ups. In addition, Cell BioEngines raised $0.25 million from Empire State Developments NY Ventures, the states venture capital arm through the Pre-Seed and Seed Matching Fund Program.

This reflects strong growth and investor confidence in our innovative approach to advancing cell therapies, particularly timely as we expand within New York State, said Dr. Ajay Vishwakarma, Founder and CEO.

The funds will support our first multicenter clinical trial, aimed at hematological cancer patients unable to find a donor and seeking an alternative to HLA-haploidentical blood stem cell transplants. CBE-101 represents a novel approach with expanded cord blood-derived hematopoietic cell therapy, aligned with Cell BioEngines' vision to deliver 'off-the-shelf' cell-based therapies to patients, he added.

About Cell BioEngines

Cell BioEngines, Inc., founded in Dec 2022, is a clinical-stage biotech company focused on developing allogeneic 'off-the-shelf' stem cell-derived therapies as drugs for human disease treatment. The company leverages its proprietary platform technology using universal 'non-gene-modified' donor blood stem cells obtained from umbilical cord to produce clinical grade cells at scale.

For more information about Cell BioEngines, and to learn more the latest Company developments, please visit http://www.cellbioengines.com

Contact

Mark Joubert., J.D. Chief Legal Officer Cell BioEngines, Inc info@cellbioengines.com

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Cell BioEngines Secures an Additional $2 Million in Funding - GlobeNewswire

A German man is reportedly the seventh person in history to be cured of HIV, according to researchers who will present the information at the 2024 International AIDS Conference in Munich, Germany.

Multiple tests given to the German man were unable to detect any copies of the virus in his body following a stem cell transplant for acute myeloid leukemia that occurred in 2015, according to a report in NBC News. The man stopped taking antiretroviral medication for his HIV in 2018 and remains in remission, or a state of having no virus present in the body.

The man has chosen to remain anonymous, but did issue a statement about his medical condition. A healthy person has many wishes, he said, a sick person only one.

The longer we see these HIV remissions without any HIV therapy, the more confidence we can get that were probably seeing a case where we really have eradicated all competent HIV, Dr. Christian Gaebler, a physician and scientist at the Charit-Universittsmedizin Berlin, told NBC News.

While any cure news is always welcomed both in the HIV community and to those outside it, the German mans case is emblematic of a trend that is proving hard to replicate for the 39 million people living with HIV worldwide. In each of the seven cases, according to NBC News, the cure came as the result of stem cell treatments for people living with HIV who had developed blood cancer. Such stem cell transplants are toxic and can be fatal, as NBC News, making it unethical as a treatment for the overwhelming majority of people with HIV.

When HIV enters a persons body, it functionally turns a persons immune cells into factories that make more and more copies of the virus. However, existing alongside these copies of the virus that actively attack a persons immune system is the latent HIV reservoir, a group of immune cells that have been overtaken by HIV but are not currently reproducing new copies of the virus. These dormant cells can awaken at any time, and targeting these cells is a major problem for HIV cure researchers. Often, these reservoirs are located in hard-to-reach areas, including the lymph nodes, the gut, and the brain, according to The Body, an HIV/AIDS news and information site.

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A Seventh Person Has Most Likely Been Cured of HIV Following Stem Cell Transplant - Them