Epigenetic memory and lineage specific differentiation of myoblast derived induced pluripotent stem cells

Abstract

Induced pluripotent stem (iPS) cells, reprogrammed from somatic cells with defined factors such as Oct4, Sox2, cMyc and Klf4, hold the potential to produce unlimited numbers of autologous cells to treat and model a variety of muscular dystrophies. However, the derivation of myogenic precursors from iPS cells remains elusive, and current differentiation protocols rely on multi-stage fluorescent cell sorting or the use of transgenes. Reprogrammed somatic cells exhibit epigenetic memory in the form of DNA methylation patterns and gene expression profiles characteristic of their tissue of origin. Here we show that myoblast (Mb) derived iPS cells maintain low level expression of myogenic markers, including MyoD, providing evidence that myogenic genes are not fully silenced in MB-iPSCs during the reprogramming process. In addition, Mb-iPS cells display preferential myogenic differentiation in vitro and in vivo compared to fibroblast (Fb) derived iPS cells. Exploiting this epigenetic memory, we establish a simple method for the derivation of myogenic progenitor cells from iPS cells, a critical step towards efficient cell therapy of Duchenne muscular dystrophy (DMD).