Skeletal Muscle Stem Cells from PSC-Derived Teratomas Have Functional Regenerative Capacity

Abstract

Derivation of functional skeletal muscle stem cells from pluripotent cells without genetic modification has proven elusive. Here we show that teratomas formed in adult skeletal muscle differentiate in vivo to produce large numbers of α7-Integrin+ VCAM-1+ myogenic progenitors. When FACS-purified and transplanted into diseased muscles, mouse teratoma-derived myogenic progenitors demonstrate very high engraftment potential. As few as 40,000 cells can reconstitute ∼80% of the tibialis anterior muscle volume. Newly generated fibers are innervated, express adult myosins, and ameliorate dystrophy-related force deficit and fatigability. Teratoma-derived myogenic progenitors also contribute quiescent PAX7+ muscle stem cells, enabling long-term maintenance of regenerated muscle and allowing muscle regeneration in response to subsequent injuries. Transcriptional profiling reveals that teratoma-derived myogenic progenitors undergo embryonic-to-adult maturation when they contribute to the stem cell compartment of regenerated muscle. Thus, teratomas are a rich and accessible source of potent transplantable skeletal muscle stem cells. VIDEO ABSTRACT.

Human iPS Cells Derived Skeletal Muscle Progenitor Cells Promote Myoangiogenesis and Restore Dystrophin in Duchenne Muscular Dystrophic Mice

“…In the present study, we found MPC induced by Givi exhibited superior migration and proliferation capabilities compared with human myoblasts and control MPC generated by CHIR99021 and FGF. Go analysis further showed upregulation of cell migration related genes enabling them to migrate to distant injured muscle (10). In our data, genes related to migration were significantly upregulated with Givi treatment.…”

“…These observations support that Givi-MPC had anti-inflammatory effects upon transplantation in CTX injured muscle suggesting that properties of MPC depend on the source of reprogramming molecule. Besides immediate effects on engraftment and differentiation, the long-term maintenance of newly formed skeletal muscle is ultimately dependent on the ability of the transplanted MPCs to contribute to the skeletal muscle stem cell pool (10). Here we observed Givi-MPC derived Pax7 positive cells under basal lamina upon transplantation, and with subsequent reinjury the Givi-MPC contributed to secondary regeneration in the Mdx/SCID mice.…”

“…Murine Lbax1 + embryonic muscle progenitors expressed ITGA4 (26). It has been reported that teratoma derived MPC possessed high engraftment efficiency in muscle dystrophy model (10). However, the mechanism of upregulation of ITGA4 by Givi and migration medicated by ITGA4 need further study.…”

“…High percentage of Pax7 positive MPC can be generated from hiPSC by small molecules (CHIR99021, LDN19389 and FGF) (7,8), but their limited engraftment was observed in vivo upon transplantation (9). Interestingly, it has been recently reported that MPC can be generated from teratoma which showed high engraftment efficiency in muscle dystrophy model (10). However, human teratoma derived MPC poses safety concerns for clinical application.…”

Immune Responses to Human Induced Pluripotent Stem Cells and their Derived Myogenic Progenitors Are Mediated by Different Mechanisms in Humanized Mice

“…Moreover, the different differentiation protocols already published for the generation of MPCs from iPSCs will also need to be evaluated for their ability to evade the immune system (Chan et al, 2018;Shelton et al, 2016;van der Wal et al, 2018). It also remains to be determined if the presence of autologous T cells can impact long-term engraftment (more than 4 weeks).…”