Hidetoshi Sakurai ^1* Masatoshi Suzuki ^2* Atsushi Asakura ^3*

• ¹ Center for iPS Cell Research and Application, Kyoto University, Kyoto, Kyōto, Japan
• ² Stem Cell & Regenerative Medicine Center, University of Wisconsin-Madison, Madison, Wisconsin, United States
• ³ Stem Cell Institute, Medical School, University of Minnesota, Minneapolis, Minnesota, United States

Skeletal muscle is a highly regenerative tissue in the vertebrate body. This skeletal muscle regenerative capacity is mediated by muscle satellite cells (MuSCs), a stem cell population within skeletal muscle [1,2]. While MuSCs display some non-muscle differentiation potential, such as adipocytes, osteocytes, and fibroblasts in vitro or in some diseased environments [3], their primary differentiation fate in normal muscle regeneration is skeletal muscle cells. MuSCs usually display a mitotically quiescent state and reside on the myofibers. However, during muscle regeneration, MuSCs are activated, exit the quiescent state, and give rise to myogenic precursor cells. After several rounds of cell proliferation, these myogenic precursor cells exit the cell cycle and fuse with each other to contribute to the newly formed myofibers. MuSC-derived myogenic precursor cells or myoblasts expanded ex vivo can be utilized for myoblast-mediated cell therapy for skeletal muscle diseases, including Duchenne muscular dystrophy (DMD) when injected into damaged myofibers via integration into myofibers [4][5][6][7]. However, there are significant limitations to treatment in humans. The number of MuSCs and myoblasts available from human biopsies is limited. In addition, low cell viability and low contribution of transplanted cells have hindered their practical use in patients [4,6,7].Human induced pluripotent stem cells (hiPSCs) are a type of pluripotent stem cells originally derived from adult somatic cells. These cells are genetically initialized to an embryonic stem cell (ESC)-like pluripotent state by expressing genes and factors that are essential for maintaining the characteristic properties of pluripotent stem cells. hiPSCs can be generated from human somatic cells from various tissues [8][9][10]. They are capable of self-renewal and can give rise to any cell type, including skeletal muscle cells and MuSCs, both in vitro and in vivo. Therefore, hiPSCderived myogenic cells are a source of myogenic precursor cells that repair injured or diseased or aged skeletal muscle in patients after transplantation [11]. In addition, the ability to capture the genetic diversity of different inherent muscle diseases and age-related muscle atrophy in an accessible culture system makes hiPSCs an attractive model source for generating myogenic cells for drug screening [11]. This research topic aims to highlight the progress of research on disease modeling using iPSCs and iPSC-based cell therapy in the field of skeletal muscle diseases. In particular, collecting technical tips for successful induction protocols of iPSC-derived skeletal muscle [12][13][14] suitable for regenerative medicine and in vitro iPSC-based disease modeling is critical for understanding the molecular and cellular mechanisms of disease pathogenesis as well as drug screening.Five primary research or review manuscripts were published on this research topic. In the first manuscript, Hamer and Rossi summarized the protocols to improve the generation, purification, and maturation of iPSC-derived myogenic cells for novel therapeutic applications [Hamer and Rossi]. Fibro/adipogenic progenitors (FAPs) residing in skeletal muscle play essential roles in skeletal muscle homeostasis and regeneration via secreted molecules and remodeling of extracellular matrix [15]. In diseased environments, FAPs give rise to adipogenic, osteogenic, or fibroblastic cells that significantly modulate normal muscle function. The second manuscript, by Zhao and Ikeya, summarized the current progress of the developmental origins and functions of FAPs as stromal cells of the muscle connective tissue (MCT) and the FAP-mediated heterotopic ossification causing the rare genetic disorder fibrodysplasia ossificans progressive (FOP) [16;Zhao and Ikeya]. In addition, this manuscript provides novel insights into the heterotopic ossification from patient-derived iPSCs. The third manuscript, by Xie et al., uncovered the molecular mechanism by which leukemia inhibitory factor (LIF) promotes the self-renewal and proliferation of MuSCs [Xie et al.]. Treatment with LIF also enhances the engraftment capability of MuSCs following injection into the skeletal muscle of DMD model mdx mice, suggesting the beneficial effect of LIF for hiPSC-derived MuSC transplantation therapy. The mutations of superoxide dismutase 1 (SOD1) gene have been known as a genetic cause of familial amyotrophic lateral sclerosis (ALS), a progressive neuromuscular disease without cure [17]. In the fourth manuscript, Couturier et al. reported that hiPSC-derived myogenic cells carrying the SOD1 D90A mutation display a reduction of several myogenic markers, including modulation of nuctic acetylcholine receptor (nAChR) cluster expression and the function, causing the morphological alteration of sarcomeres in myotubes [Couturier et al.]. Therefore, the authors introduced the novel hiPSC-derived neuromuscular model for ALS [18,19]. As humans age, changes in the composition of blood circulating factors are thought to contribute to the decline in muscle mass and strength. In the fifth manuscript, Tey et al. reported that supplementation with serum from aged rats significantly reduced cell proliferation, myotube formation, and myofiber maturation, significantly increased cell death, and induced transcriptomic changes in both ESC-and iPSCderived myogenic cells, providing therapeutic applications to prevent age-related muscle weakness [Tey et al.]. This series of five articles highlights the high quality of manuscripts published in the research topic of the Stem Cell Research section of Frontiers in Cell and Developmental Biology and reveals a research field that is moving forward at a remarkable pace.