Durham, NC (PRWEB) September 09, 2013

As stem cell clinical trials for multiple sclerosis (MS) patients become more common, it is crucial for researchers to understand the biologic changes and therapeutic effects of older donor stem cells. A new study appearing in the latest issue of STEM CELLS Translational Medicine is the first to demonstrate that, in fact, adipose-derived stem cells donated by older people are less effective than cells from their younger counterparts.

MS is a neurodegenerative disease characterized by inflammation and scar-like lesions throughout the central nervous system (CNS). There is no cure and no treatment eases the severe forms of MS. But previous studies on animals have shown that transplantation of mesenchymal stem cells (MSCs) holds promise as a therapy for all forms of MS. The MSCs migrate to areas of damage, release trophic (cell growth) factors and exert neuroprotective and immunomodulatory effects to inhibit T cell proliferation.

MS-related clinical trials have all confirmed the safety of autologous MSC therapy. However what is unclear is whether MSCs derived from older donors have the same therapeutic potential as those from younger ones.

"Aging is known to have a negative impact on the regenerative capacity of most tissues, and human MSCs are susceptible to biologic aging including changes in differentiation potential, proliferation ability and gene expression. These age-related differences may affect the ability of older donor cells to migrate extensively, provide trophic support, persist long-term and promote repair mechanisms," said Bruce Bunnell, Ph.D., of Tulane Universitys Center for Stem Cell Research and Regenerative Medicine. He served as lead author of the study, conducted by a team composed of his colleagues at Tulane.

In their study, mice were induced with chronic experimental autoimmune encephalomyelitis (EAE) and treated before disease onset with human adipose-derived MSCs derived from younger (less than 35 years) or older (over age 60) donors. The results corroborated previous studies suggesting that older donors are less effective than their younger counterparts.

"We found that, in vitro, the stem cells from the older donors failed to ameliorate the neurodegeneration associated with EAE. Mice treated with older donor cells had increased inflammation of the central nervous system, demyelination leading to an impairment in movement, cognition and other functions dependent on nerves, and a proliferation of splenocytes [white blood cells in the spleen], compared to the mice receiving cells from younger donors," Dr. Bunnell noted.

In fact, the T cell proliferation assay results in the study indicated that older MSCs might actually stimulate the proliferation of the T cells, while younger stem cells are capable of inhibiting the proliferation of T cells. (T cells are a type of white blood cell in the bodys immune system that help fight off disease and harmful substances.)

As such, Dr. Bunnell said, "A decrease in T cell proliferation would result in a decreased number of T cells available to attack the CNS in the mice, which directly supports the results showing that the CNS damage and inflammation is less severe in the young MSC-treated mice than in the old MSC-treated mice."

"This study in an animal model of MS is the first to demonstrate that fat-derived stem cells from older human donors have less therapeutic effectiveness than cells from young donors," said Anthony Atala, M.D., editor of STEM CELLS Translational Medicine and director of the Wake Forest Institute for Regenerative Medicine. "The results point to a potential need to evaluate cell therapy protocols for late-onset multiple sclerosis patients."

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Study Indicates Benefits of Stem Cells in Treating MS Declines With Donor’s Age

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Scientists at A*STAR's Genome Institute of Singapore (GIS), in collaboration with their counterparts from Canada, Hong Kong and US, have discovered a protein mediator SON plays a critical role in the health and proper functioning of human embryonic stem cells (hESCs) . This finding was reported on 8th September 2013 in the advanced online issue of the prestigious science journal Nature Cell Biology.

Correct expression of genes is essential for a cell to stay alive and to perform other cellular and physiological functions. During gene expression, DNA is first converted into RNA transcript and then some parts of it are removed while others are joined before the trimmed RNA transcript can be translated into proteins. This process of cutting and joining different pieces of RNA is called splicing, and the proteins that mediate splicing are known as splicing factors. Mutations in splicing factors can cause diseases such as myotonic dystrophy and cancer. Even though hESCs have been studied extensively over the last decade due to their potential to differentiate into cell-types of potential clinical applications, little is known about the role that splicing plays in the regulation of pluripotency in these cells.

Scientists at the GIS followed their previous study on a genome-wide investigation of gene functions in hESCs, which was published in Nature [Chia et al. 2010. 468(7321):316-20], and found that splicing factors, such as the protein known as SON, are key regulators of hESC maintenance.

SON was discovered to be essential for converting differentiated cells into pluripotent stem cells. In addition, SON promotes correct splicing of a particular group of RNAs, including those coding for essential hESC regulators, and thereby helps hESCs to survive in an undifferentiated state. Moreover, the authors showed that silencing of SON induced new transcript isoforms that seemed to be non-functional in hESCs.

The study, led by GIS Executive Director Prof Ng Huck Hui, establishes an initial connection between splicing and pluripotency in hESCs and contributes to the comprehensive understanding of the nature of hESCs. Besides its role in hESCs, SON was previously found to be involved in the development of leukemia and influenza virus infection.

Prof Ng Huck Hui said, "Maintenance and differentiation of human embryonic stem cells are governed by an intricate network that comprises diverse cellular processes. In the past, we had been focusing primarily on transcriptional regulation. In our new study, it is clear that splicing contributes to the unique cellular state of hESCs and this can be explained in part through the function of a protein known as SON. SON regulates the precise splicing of specific transcripts which are important for pluripotency. A systematic dissection of the different pathways required for maintenance of pluripotency can eventually guide us in engineering novel cellular states in the laboratory."

"In this new manuscript in Nature Cell Biology, Ng Huck Hui and his colleagues continue to cement their position at the forefront of pluripotency research worldwide," said Dr Alan Colman, the former Executive Director of the Singapore Stem Cell Consortium. "The distinctive feature of human embryonic stem cells is their ability to either self renew or alternatively, given the right conditions, to differentiate into all the cell types that comprise the adult body. In previous work, the team had uncovered a number of unique transcription factors that mediate the maintenance of pluripotency via binding to genomic DNA. In this latest publication, they reveal a novel mechanism where SON, a protein localized to nuclear speckles, regulates the proper splicing of transcripts encoding pluripotency regulators such as OCT4, PRDM14, E4F1 and MED24, and ensures cell survival and maintenance of pluripotency in hESC (and by extrapolation, presumably human induced pluripotent stem cells also)."

Prof Eran Meshorer from the Department of Genetics at the Hebrew University of Jerusalem added, "In recent years, a growing number of papers focusing on the transcriptional regulators that control embryonic stem cell biology have been published. However, the link between RNA splicing and pluripotency has only very recently emerged and the factors that regulate splicing and alternative splicing in ES cells are unknown. The paper by Ng Huck Hui and colleagues now shows that the splicing regulator SON, previously identified in a screen conducted by the same group for novel pluripotency-related factors, regulates the splicing of several key pluripotency genes, linking splicing with stem cell biology and pluripotency. This paper provides a major step towards a more complete understanding of the mechanisms controlling pluripotency and self-renewal, and calls for the identification of additional splicing regulators in ES cells. It is also tempting to speculate that SON and other splicing-related proteins may assist in converting somatic cells into pluripotent cells in the process of reprogramming." Prof Meshorer is the winner of the 2013 Sir Zelman Cowen Universities Fund Prize for Medical Research for the extensive and groundbreaking work undertaken in his laboratory to shed light on pluripotency.

Explore further: Researchers ID proteins key in stem cell production

Read more from the original source:
Scientists discover new RNA processing pathway important in human embryonic stem cells

Discovery of RNA regulator could lead to a better understanding of diseases like cancer and influenza

Singapore, Sept 9, 2013 - (ACN Newswire) - Scientists at A*STAR's Genome Institute of Singapore (GIS), in collaboration with their counterparts from Canada, Hong Kong and US, have discovered a protein mediator SON plays a critical role in the health and proper functioning of human embryonic stem cells (hESCs). This finding was reported on 8th September 2013 in the advanced online issue of the prestigious science journal Nature Cell Biology.

Correct expression of genes is essential for a cell to stay alive and to perform other cellular and physiological functions. During gene expression, DNA is first converted into RNA transcript and then some parts of it are removed while others are joined before the trimmed RNA transcript can be translated into proteins. This process of cutting and joining different pieces of RNA is called splicing, and the proteins that mediate splicing are known as splicing factors. Mutations in splicing factors can cause diseases such as myotonic dystrophy and cancer. Even though hESCs have been studied extensively over the last decade due to their potential to differentiate into cell-types of potential clinical applications, little is known about the role that splicing plays in the regulation of pluripotency in these cells.

Scientists at the GIS followed their previous study on a genome-wide investigation of gene functions in hESCs, which was published in Nature [Chia et al. 2010. 468(7321):316-20], and found that splicing factors, such as the protein known as SON, are key regulators of hESC maintenance.

SON was discovered to be essential for converting differentiated cells into pluripotent stem cells[1]. In addition, SON promotes correct splicing of a particular group of RNAs, including those coding for essential hESC regulators, and thereby helps hESCs to survive in an undifferentiated state. Moreover, the authors showed that silencing of SON induced new transcript isoforms[2] that seemed to be non-functional in hESCs.

The study, led by GIS Executive Director Prof Ng Huck Hui, establishes an initial connection between splicing and pluripotency in hESCs and contributes to the comprehensive understanding of the nature of hESCs. Besides its role in hESCs, SON was previously found to be involved in the development of leukemia and influenza virus infection.

Prof Ng Huck Hui said, "Maintenance and differentiation of human embryonic stem cells are governed by an intricate network that comprises diverse cellular processes. In the past, we had been focusing primarily on transcriptional regulation. In our new study, it is clear that splicing contributes to the unique cellular state of hESCs and this can be explained in part through the function of a protein known as SON. SON regulates the precise splicing of specific transcripts which are important for pluripotency. A systematic dissection of the different pathways required for maintenance of pluripotency can eventually guide us in engineering novel cellular states in the laboratory."

"In this new manuscript in Nature Cell Biology, Ng Huck Hui and his colleagues continue to cement their position at the forefront of pluripotency research worldwide," said Dr Alan Colman, the former Executive Director of the Singapore Stem Cell Consortium. "The distinctive feature of human embryonic stem cells is their ability to either self renew or alternatively, given the right conditions, to differentiate into all the cell types that comprise the adult body. In previous work, the team had uncovered a number of unique transcription factors that mediate the maintenance of pluripotency via binding to genomic DNA. In this latest publication, they reveal a novel mechanism where SON, a protein localized to nuclear speckles, regulates the proper splicing of transcripts encoding pluripotency regulators such as OCT4, PRDM14, E4F1 and MED24, and ensures cell survival and maintenance of pluripotency in hESC (and by extrapolation, presumably human induced pluripotent stem cells also)."

Prof Eran Meshorer from the Department of Genetics at the Hebrew University of Jerusalem added, "In recent years, a growing number of papers focusing on the transcriptional regulators that control embryonic stem cell biology have been published. However, the link between RNA splicing and pluripotency has only very recently emerged and the factors that regulate splicing and alternative splicing in ES cells are unknown. The paper by Ng Huck Hui and colleagues now shows that the splicing regulator SON, previously identified in a screen conducted by the same group for novel pluripotency-related factors, regulates the splicing of several key pluripotency genes, linking splicing with stem cell biology and pluripotency. This paper provides a major step towards a more complete understanding of the mechanisms controlling pluripotency and self-renewal, and calls for the identification of additional splicing regulators in ES cells. It is also tempting to speculate that SON and other splicing-related proteins may assist in converting somatic cells into pluripotent cells in the process of reprogramming." Prof Meshorer is the winner of the 2013 Sir Zelman Cowen Universities Fund Prize for Medical Research for the extensive and groundbreaking work undertaken in his laboratory to shed light on pluripotency.

[1] Cells that have the ability to differentiate in different cell types. [2] Different forms of the same gene.

Continued here:
Singapore Scientists Discover New RNA Processing Pathway Important in Human Embryonic Stem Cells

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Research and Markets: Cancer Stem Cells Drug Pipeline Update 2013