Stem Cell and Regenerative Biology
Principal investigators :
David A. Sassoon, Ph.D. Research Director & Giovanna Marazzi, MD
Research team :
Faculty: UMR_S787 Therapy of Striated Muscle Diseases
Jean Remy Courbard, Vanessa Besson, Alessia Mazzola, Luigi Formicola, Anne Lyse Denizot, Rosa Maria Correra.
The ability of tissues to regenerate and maintain integrity relies in large part upon stem/progenitor cell competence. In the case of certain diseases, and as a normal process of aging, stem cells decrease in number and/or lose regenerative capacity. Resident stem/progenitor cells have been indentified in almost all adult tissues. Depending upon tissue identity, stem cells are proliferative, such as the gut, or quiescent unless activated for tissue repair. In addition to different cell cycle behaviours, adult stem/progenitor cells are found in anatomically discrete structures (bulge cells, intestinal crypt cells) or dispersed throughout the tissue with no discernable niche (skeletal muscle, bone). Lastly, certain tissues show remarkable regenerative capacities whereas others tissues fail to regenerate in response to injury despite the demonstrated presence of stem cells. It is this last point that is the most challenging for regenerative medicine and stem cell research and provides a central focus of the proposed research. How is it that humans share such similar genetic and cellular properties to lower vertebrates such as the fish or newt, and yet have such limited abilities for tissue repair by comparison? If stem cells are present and functional in a zebra fish heart, can we ‘wake them up’ in the murine or human heart and would there be unanticipated negative consequences? Less far fetched is why regeneration of skin or muscle is more efficient in the young versus the elderly? We propose that a multidisciplinary approach to adult stem cells in a variety of tissues will shed significant light on this important question.
We are undertaking a multidisciplinary approach to examine an array of stem cell lineages to further our understanding of how PW1 controls stem cell activation, cell fate and selfrenewal and integrates these functions into cell stress responses such as injury. We will use our models in combination with additional genetic tools being developed in parallel to explore and identify stem cell niches in tissues for which stem cell identity has remained elusive such as the heart, which is a major focus in the context of ICAN in close collaboration with several ICAN teams. While this research is primarily fundamental in nature, we will also test whether interference in PW1 expression can improve stem cell performance in tissues that typically display poor regenerative capacity, notably the CNS and heart (see Figure 1).
The identification of ‘global’ stem cell markers has significance insomuch that it allows for the generation of tools to easily isolate stem cells from the adult using cell sorting techniques and can be used to identify stem cells easily within their niche in vivo. Given the small number of stem cells present in most tissues (ranging from 0.01% to 5.0%), it remains a major challenge to isolate sufficient numbers for biochemical and molecular analyses as well as for therapeutic approaches. One approach is to expand stem cells in culture, however, whereas stem cells are able to undergo many divisions in vivo, they often undergo growth arrest and/or lose stem cell competence (do not self renew) in culture. It is possible that a similar process underlying the decline in stem cell competence is occurring with age. Two likely explanations for this are that 1) stem cells undergo an autonomous change and become reprogrammed over time (epigenetic) and 2) the stem cell environment changes such that critical factors that favour stem cell growth are no longer present or negative factors begin to be expressed. The net result is that stem cells can no longer be mobilized in response to injury. Our current research efforts explore both of these hypotheses and bring to bear on the problem some novel tools that have been recently generated by our laboratory.
This general aim also fits into the overall aim of the FP7 project that Dr Sassoon coordinated entitled EndoSTEM.
Our research is focused upon adult stem cells in a number of tissues ranging from the skin to muscle and vasculature to the central nervous system and heart. Our previous work led to the identification of a regulator of skeletal muscle stem cells, called PW1/Peg3, that is involved in the regulation of 2 key cell stress pathwaysp53 and inflammation.
Dr. Sassoon received his Ph.D. from Columbia University (New York) and performed his postdoctoral studies at the Pasteur Institute (Paris). He was a Full Professor at Mt. Sinai Medical School until 2006 and then accepted a directorship at Paris Sorbonne (Paris VI) in collaboration with INSERM to run a basic research unit on stem/developmental cell biology. His long-standing interests are in developmental and stem cell biology with an emphasis on skeletal muscle although he has made significant contributions to the field of endocrine disruption, most notably regarding the catastrophic effects of synthetic estrogen exposure in utero leading to adult onset disease. More recently, his team has focused upon adult stem cells in a number of tissues including skin, CNS and heart. Previous work led to the identification of a regulator of skeletal muscle stem cells, called PW1 (also known as Peg3) that is involved in the regulation of cell stress pathways. PW1/Peg3 not only defines a novel population of skeletal muscle stem cells but can be used to identify every adult stem cell niche investigated to date. His team has undertaken a multidisciplinary approach to examine an array of stem cell lineages to further our understanding of how PW1 controls stem cell activation, cell fate and self-renewal. While his research is fundamental in nature, his team is testing whether interference in PW1/Peg3 expression can improve stem cell performance in tissues that typically display poor regenerative capacity, notably the CNS and heart. This work promises to have high impact for regenerative medicine and the development of stem cell directed therapies. In this regard, Dr. Sassoon coordinates a EC-funded 15 partner international consortium (Endostem) designed to identify novel therapeutics for mobilizing endogenous stem/progenitor cells (http://www.endostem.eu/ ) and is a recent recipient of a multipartner Transatlantic Network of Excellence grant from the Fondation Leducq which he coordinates focused on cardiac stem cell biology (http://www.fondationleducq.org/nivel2.aspx?idsec=1360 ).