Epigenetic Rejuvenation of Mesenchymal Stromal Cells Derived from Induced Pluripotent Stem Cells

摘要

class="head no_bottom_margin" id="sec1title">IntroductionMesenchymal stromal cells (MSCs) are heterogeneous cell preparations and only a small subpopulation often referred to as “mesenchymal stem cells” possesses multilineage differentiation potential (). MSC preparations are greatly affected by starting material, such as bone marrow (BM) or adipose tissue (AT), and cell-culture media. Furthermore, they acquire functional changes during culture expansion ending in replicative senescence (). So far, MSCs are scarcely defined by fibroblastoid plastic adherent growth, a panel of nonspecific surface markers, and their capacity to differentiate toward adipogenic, osteogenic, and chondrogenic lineages ().In this regard, induced pluripotent stem cells (iPSCs) converge to a better-defined ground state of pluripotency (). They can be differentiated into all cell types of the organism and—while in pluripotent state—cultured virtually indefinitely without signs of replicative senescence. Epigenetic profiles, such as DNA methylation (DNAm) patterns, are reorganized during reprogramming of somatic cells into iPSCs and closely resemble those of embryonic stem cells (ESCs) (). In particular, senescence-associated DNAm, which is acquired during in vitro expansion (), and age-related DNAm, which accumulate during aging of the organism (), are reversed to ground state. In comparison to primary cells, iPSCs are therefore better defined and offer a good starting point for large-scale generation of standardized derivatives, such as iPSC-derived MSCs (iPS-MSCs).Several groups described strategies to derive MSC-like cells from either ESCs () or iPSCs (). These approaches were based on coculture with primary MSCs, growth factor combinations, or spontaneous differentiation in embryoid bodies (EBs). So far, it has not been analyzed whether DNAm patterns of iPS-MSCs resemble those of primary MSCs.