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Activation of non-myogenic mesenchymal stem cells during the disease progression in dystrophic dystrophin/utrophin knockout mice.
Hum Mol Genet. 2015 Jul 01; 24(13):3814-29.HM

Abstract

Ectopic calcification as well as fatty and fibrotic tissue accumulation occurs in skeletal muscle during the disease progression of Duchenne muscular dystrophy (DMD), a degenerative muscle disorder caused by mutations in the dystrophin gene. The cellular origin and the environmental cues responsible for this ectopic calcification, fatty and fibrotic infiltration during the disease progression, however, remain unknown. Based on a previously published preplate technique, we isolated two distinct populations of muscle-derived cells from skeletal muscle: (i) a rapidly adhering cell population, which is non-myogenic, Pax7(-) and express the mesenchymal stem cell (MSC) marker platelet-derived growth factor receptor alpha; hence, we termed this population of cells non-myogenic MSCs (nmMSCs); and (ii) a slowly adhering cell population which is Pax7(+) and highly myogenic, termed muscle progenitor cells (MPCs). Previously, we demonstrated that the rapid progression of skeletal muscle histopathologies in dystrophin/utrophin knockout (dys(-/-) utro(-/-) dKO) mice is closely associated with a rapid depletion of the MPC population pool. In the current study, we showed that in contrast to the MPCs, the nmMSCs become activated during the disease progression in dKO mice, displaying increased proliferation and differentiation potentials (adipogenesis, osteogenesis and fibrogenesis). We also found that after co-culturing the dKO-nmMSCs with dKO-MPCs, the myogenic differentiation potential of the dKO-MPCs was reduced. This effect was found to be potentially mediated by the secretion of secreted frizzled-related protein 1 by the dKO-nmMSCs. We therefore posit that the rapid occurrence of fibrosis, ectopic calcification and fat accumulation, in dKO mice, is not only attributable to the rapid depletion of the MPC pool, but is also the consequence of nmMSC activation. Results from this study suggest that approaches to alleviate muscle weakness and wasting in DMD patients should not only target the myogenic MPCs but should also attempt to prevent the activation of the nmMSCs.

Authors+Show Affiliations

Stem Cell Research Center, Department of Orthopaedic Surgery and.Stem Cell Research Center, Department of Orthopaedic Surgery and.Stem Cell Research Center, Department of Orthopaedic Surgery and.Stem Cell Research Center, Department of Orthopaedic Surgery and.Stem Cell Research Center, Department of Orthopaedic Surgery and Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA jhuard@pitt.edu.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

Language

eng

PubMed ID

25859011

Citation

Sohn, Jihee, et al. "Activation of Non-myogenic Mesenchymal Stem Cells During the Disease Progression in Dystrophic Dystrophin/utrophin Knockout Mice." Human Molecular Genetics, vol. 24, no. 13, 2015, pp. 3814-29.
Sohn J, Lu A, Tang Y, et al. Activation of non-myogenic mesenchymal stem cells during the disease progression in dystrophic dystrophin/utrophin knockout mice. Hum Mol Genet. 2015;24(13):3814-29.
Sohn, J., Lu, A., Tang, Y., Wang, B., & Huard, J. (2015). Activation of non-myogenic mesenchymal stem cells during the disease progression in dystrophic dystrophin/utrophin knockout mice. Human Molecular Genetics, 24(13), 3814-29. https://doi.org/10.1093/hmg/ddv125
Sohn J, et al. Activation of Non-myogenic Mesenchymal Stem Cells During the Disease Progression in Dystrophic Dystrophin/utrophin Knockout Mice. Hum Mol Genet. 2015 Jul 1;24(13):3814-29. PubMed PMID: 25859011.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Activation of non-myogenic mesenchymal stem cells during the disease progression in dystrophic dystrophin/utrophin knockout mice. AU - Sohn,Jihee, AU - Lu,Aiping, AU - Tang,Ying, AU - Wang,Bing, AU - Huard,Johnny, Y1 - 2015/04/09/ PY - 2015/01/14/received PY - 2015/04/07/accepted PY - 2015/4/11/entrez PY - 2015/4/11/pubmed PY - 2016/4/29/medline SP - 3814 EP - 29 JF - Human molecular genetics JO - Hum. Mol. Genet. VL - 24 IS - 13 N2 - Ectopic calcification as well as fatty and fibrotic tissue accumulation occurs in skeletal muscle during the disease progression of Duchenne muscular dystrophy (DMD), a degenerative muscle disorder caused by mutations in the dystrophin gene. The cellular origin and the environmental cues responsible for this ectopic calcification, fatty and fibrotic infiltration during the disease progression, however, remain unknown. Based on a previously published preplate technique, we isolated two distinct populations of muscle-derived cells from skeletal muscle: (i) a rapidly adhering cell population, which is non-myogenic, Pax7(-) and express the mesenchymal stem cell (MSC) marker platelet-derived growth factor receptor alpha; hence, we termed this population of cells non-myogenic MSCs (nmMSCs); and (ii) a slowly adhering cell population which is Pax7(+) and highly myogenic, termed muscle progenitor cells (MPCs). Previously, we demonstrated that the rapid progression of skeletal muscle histopathologies in dystrophin/utrophin knockout (dys(-/-) utro(-/-) dKO) mice is closely associated with a rapid depletion of the MPC population pool. In the current study, we showed that in contrast to the MPCs, the nmMSCs become activated during the disease progression in dKO mice, displaying increased proliferation and differentiation potentials (adipogenesis, osteogenesis and fibrogenesis). We also found that after co-culturing the dKO-nmMSCs with dKO-MPCs, the myogenic differentiation potential of the dKO-MPCs was reduced. This effect was found to be potentially mediated by the secretion of secreted frizzled-related protein 1 by the dKO-nmMSCs. We therefore posit that the rapid occurrence of fibrosis, ectopic calcification and fat accumulation, in dKO mice, is not only attributable to the rapid depletion of the MPC pool, but is also the consequence of nmMSC activation. Results from this study suggest that approaches to alleviate muscle weakness and wasting in DMD patients should not only target the myogenic MPCs but should also attempt to prevent the activation of the nmMSCs. SN - 1460-2083 UR - https://www.unboundmedicine.com/medline/citation/25859011/Activation_of_non_myogenic_mesenchymal_stem_cells_during_the_disease_progression_in_dystrophic_dystrophin/utrophin_knockout_mice_ L2 - https://academic.oup.com/hmg/article-lookup/doi/10.1093/hmg/ddv125 DB - PRIME DP - Unbound Medicine ER -