title: Intrinsic cell memory reinforces myogenic commitment of pericyte-derived iPSCs.
abstract: Mesoangioblasts (MABs) are a subset of muscle-derived pericytes able to restore dystrophic phenotype in mice and dogs. However, their lifespan is limited and they undergo senescence after 25-30 population doublings. Recently, induced pluripotent stem cells (iPSCs) generated from reprogrammed fibroblasts have been demonstrated to have in vitro and in vivo myogenic potential when sorted for the SM/C-2.6 antigen. Furthermore, chimeric mice from mdx-iPSCs (DYS-HAC) cells showed tissue-specific expression of dystrophin. Nevertheless, myogenic differentiation protocols and the potential of iPSCs generated from different cell sources still present unanswered questions. Here we show that iPSCs generated from prospectively sorted MABs (MAB-iPSCs) are pluripotent as fibroblast-derived iPSCs (f-iPSCs). However, both teratoma formation and genetic cell manipulation assays identify a durable epigenetic memory in MAB-iPSCs, resulting in stronger myogenic commitment. Striated muscle tissue accounts for up to 70% of MAB-iPSC teratomas. Moreover, transfection with Pax3 and Pax7 induces a more robust myogenic differentiation in MAB-iPSCs than in f-iPSCs. A larger amount of CD56(+) progenitors can be sorted from the MAB-iPSCs differentiating pool and, after transplantation into αsg-KO mice, can efficiently participate to skeletal muscle regeneration and restore αsg expression. Our data strongly suggest that iPSCs are a heterogeneous population and, when generated from myogenic adult stem cells, they exhibit a stronger commitment, paving the way for creating custom-made cell protocols for muscular dystrophies.
authors.affiliation: Translational Cardiomyology, Stem Cell Institute, Katholieke Universiteit Leuven, Herestraat 49, Leuven, Belgium.
authors.forename: Mattia
authors.initials: M
authors.lastname: Quattrocelli
authors.forename: Giacomo
authors.initials: G
authors.lastname: Palazzolo
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Floris
authors.forename: Patrick
authors.initials: P
authors.lastname: Schöffski
authors.forename: Luigi
authors.initials: L
authors.lastname: Anastasia
authors.forename: Aldo
authors.initials: A
authors.lastname: Orlacchio
authors.forename: Thierry
authors.initials: T
authors.lastname: Vandendriessche
authors.forename: Marinee K L
authors.initials: MK
authors.lastname: Chuah
authors.forename: Giulio
authors.initials: G
authors.lastname: Cossu
authors.forename: Catherine
authors.initials: C
authors.lastname: Verfaillie
authors.forename: Maurilio
authors.initials: M
authors.lastname: Sampaolesi
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D019002:CD56 Antigen / Q000032:analysis; D002454:Cell Differentiation; D049109:Cell Proliferation; D004251:DNA Transposable Elements; D004195:Disease Models, Animal; D044127:Epigenesis, Genetic; D057026:Induced Pluripotent Stem Cells / Q000166:cytology* / Q000637:transplantation; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000502:physiology; D009137:Muscular Dystrophy, Animal / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D020286:Pericytes / Q000166:cytology*; D012038:Regeneration; D049031:Sarcoglycans / Q000172:deficiency / Q000378:metabolism; D014162:Transfection
chemical_list: D019002:CD56 Antigen; D004251:DNA Transposable Elements; D049031:Sarcoglycans