Establishment of stably expandable induced myogenic stem cells by four transcription factors

Abstract

Life-long regeneration of healthy muscle by cell transplantation is an ideal therapy for patients with degenerative muscle diseases. Yet, obtaining muscle stem cells from patients is very limited due to their exhaustion in disease condition. Thus, development of a method to obtain healthy myogenic stem cells is required. Here, we showed that the four transcription factors, Six1, Eya1, Esrrb, and Pax3, converts fibroblasts into induced myogenic stem cells (iMSCs). The iMSCs showed effective differentiation into multinucleated myotubes and also higher proliferation capacity than muscle derived stem cells both in vitro and in vivo. The iMSCs do not lose their proliferation capacity though the passaging number is increased. We further isolated CD106-negative and α7-integrin-positive iMSCs (sort-iMSCs) showing higher myogenic differentiation capacity than iMSCs. Moreover, genome-wide transcriptomic analysis of iMSCs and sort-iMSCs, followed by network analysis, revealed the genes and signaling pathways associated with enhanced proliferation and differentiation capacity of iMSCs and sort-iMSCs, respectively. The stably expandable iMSCs provide a new source for drug screening and muscle regenerative therapy for muscle wasting disease.

BM-MSC Transplantation Alleviates Intracerebral Hemorrhage-Induced Brain Injury, Promotes Astrocytes Vimentin Expression, and Enhances Astrocytes Antioxidation via the Cx43/Nrf2/HO-1 Axis

“…Several studies have described the importance of Cx43 in antioxidant stress. Inhibition of Cx43 degradation could protect cardiomyocytes exposed to hydrogen peroxide, by inhibiting oxidative stress (Lee et al, 2018). Chen et al (2017) revealed that Cx43 could regulate Nrf2/ARE signaling to resist oxidative stress injury in glomerular mesangial cells.…”

Nogo-A regulates myogenesis via interacting with Filamin-C

“…S2). Further, the expression of ERRγ, a proposed critical regulator of myogenesis 33 , was elevated in human myopathic muscles ( Fig. 5B, C).…”

“…4A, B). Previously, we have derived iMSCs from mouse embryo fibroblasts bearing potent myogenic differentiation capacity to show that iMSCs sorted according to stem cell markers (sort-iMSCs) had enhanced myogenic potential 33 . To confirm the expression of Nogo-A during myogenic differentiation, we analyzed differentiated iMSCs and sort-iMSCs, and observed enhanced Nogo-A expression ( Fig.…”

Muscle and cardiac therapeutic strategies for Duchenne muscular dystrophy: past, present, and future

“…Ito et al [ 182 ] have found that defined combinations of transcription factors (Pax3 , Mef2b, and Pitx1 or Pax7, Mef2b, and Pitx1 in embryonic fibroblasts, and Pax7 , Mef2b, and MyoD in adult fibroblasts) efficiently reprogrammed murine fibroblasts into skeletal muscle progenitor cells able to form dystrophin-positive mature muscle fibers when transplanted into mdx mice. Lee et al [ 183 ] described the method of murine fibroblasts conversion to induced myogenic stem cells (iMSCs), characterized by the effective differentiation into multinucleated myotubes and higher proliferation capacity than muscle-derived stem cells. It was demonstrated that the combination of four transcription factors, Six1, Eya1, Esrrb, and Pax3, is critical to establish iMSCs [ 183 ].…”

“…Lee et al [ 183 ] described the method of murine fibroblasts conversion to induced myogenic stem cells (iMSCs), characterized by the effective differentiation into multinucleated myotubes and higher proliferation capacity than muscle-derived stem cells. It was demonstrated that the combination of four transcription factors, Six1, Eya1, Esrrb, and Pax3, is critical to establish iMSCs [ 183 ]. Another strategy was proposed by Bar-Nur et al [ 184 ].…”