Pluripotent stem cells hold tremendous promise for the eventual development of cell therapies for muscle disease; however it has proven exceptionally difficult to derive cells with meaningful in vivo regeneration potential from unmodified wild type (WT) pluripotent stem cells. Mouse transplantation studies with WT PSC- derived cells are rare, and success in the field currently equates to generation of a few hundred fibers in a transplanted tibialis anterior muscle with 3-4,000 total fibers. We have recently discovered that when mouse PSCs are differentiated into teratomas in vivo, they generate large numbers of skeletal muscle stem cells, and these cells have tremendous in vivo functional potential, regenerating the great majority of the TA muscle with force-generating muscle fibers upon transplantation. We propose a series of studies aimed at understanding how these cells arise, what makes them unique, translating these findings to the human system, and using this knowledge to improve in vitro differentiation protocols.
Although pluripotent stem cells (PSCs) hold great promise for cell therapies for many tissues, it has proven exceptionally difficult to derive cells with in vivo skeletal muscle regeneration potential from PSCs. This study is based on the recent discovery that when PSCs differentiate as teratomas, highly transplantable skeletal muscle stem cells arise within these teratomas and can be used for skeletal muscle transplantation and regeneration. We propose a series of studies aimed at understanding how these cells arise and what makes them unique, with the aim of applying this information to in vitro differentiation of PSCs and enabling the generation of human PSC-derived muscle stem cells useful for skeletal muscle regenerative therapy.
