Tissue Engineering and Biobanking

Biography

Biography: Jean-Marc Lemaitre

Abstract

Many of the pathologies that could benefit from regenerative stem cell-based therapies are associated to aging. Emerging evidences indicates that adult stem cells exhibit functional shortcomings, including pronounced shifts in the types of mature effector cells produced as well as alterations in self-renewal capacity. Many intrinsic or extrinsic stress are able to accelerate the exhaustion of the proliferative capacity of stem cells or differentiated progenitors towards an ultimate senescencelike cell cycle arrest. Important and specific epigenetic modifications have been observed during this process, likely driving a specific gene expression –signature of cellular aging, and little is known about changes in large-scale genome organization during this aging process and or in different during senescence induced situations and its relationship with genetic instability. To further analyses this process and the relationship between replicative stress and chromatin reorganization, we followed the reorganization of chromatin dynamics features associated with senescence induction as well as the associated changes of the DNA replication program (Riviera-Mulia et al., 2017, Ogrunc et al., 2016, Prieur et al., 2016). To further understand, the interplay between genetics and epigenetics in tissue aging and to unravel molecular barriers, preventing cell rejuvenation of the age-related cellular physiology, we developed reprogramming strategies of somatic cells into induced pluripotent stem cells (iPSCs) to erase the hallmarks of cellular aging. Although this strategy provides a unique opportunity to derive patientspecific stem cells with potential application in autologous tissue replacement, limitation was revealed for elderly individuals, due to senescence described as a barrier to reprogramming that could drive genetic instability. To overcome this barrier and improve tissue regeneration, we developed an optimized reprogramming strategy that caused efficient reversing of cellular senescence and aging through reprogramming towards pluripotency. We demonstrated that iPSCs derived from senescent and centenarian fibroblasts have reset all the hallmarks of cellular aging, as telomere size, gene expression profiles, oxidative stress and mitochondrial metabolism, and are undistinguishable from hESC. Finally, we further demonstrate that re-differentiation, led to rejuvenated cells with a reset cellular physiology maintaining genetic stability, defining a new paradigm for human cell rejuvenation (Milhavet and Lemaitre 2014, Venables et al., 2013, Lapasset et al. 2011). Then we applied this knowledge to develop iPSC models for premature aging syndromes with high risk of genetic instability, to further explore the relationship between pathological and physiological aging. We will present and discuss data concerning opportunities and limits of using the iPSC technology for modelling pathologies involving replication stress, leading to senescence and ageing and genetic instability (Riviera-Mulia et al., 2017, Bouckenheimer et al., 2016, Lemey et al., 2016, Besnard et al., 2012, 2014).