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Engraftment of mesenchymal stem cells into dystrophin-deficient mice is not accompanied by functional recovery

Mesenchymal stem cell preparations have been proposed for muscle regeneration in musculoskeletal disorders. Although MSCs have great in vitro expansion potential and possess the ability to differentiate into several mesenchymal lineages, myogenesis has proven to be much more difficult to induce. We...

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Published in:Experimental cell research 2009-09, Vol.315 (15), p.2624-2636
Main Authors: Gang, Eun Ji, Darabi, Radbod, Bosnakovski, Darko, Xu, Zhaohui, Kamm, Kristine E., Kyba, Michael, Perlingeiro, Rita C.R.
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container_issue 15
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container_title Experimental cell research
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creator Gang, Eun Ji
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description Mesenchymal stem cell preparations have been proposed for muscle regeneration in musculoskeletal disorders. Although MSCs have great in vitro expansion potential and possess the ability to differentiate into several mesenchymal lineages, myogenesis has proven to be much more difficult to induce. We have recently demonstrated that Pax3, the master regulator of the embryonic myogenic program, enables the in vitro differentiation of a murine mesenchymal stem cell line (MSCB9-Pax3) into myogenic progenitors. Here we show that injection of these cells into cardiotoxin-injured muscles of immunodeficient mice leads to the development of muscle tumors, resembling rhabdomyosarcomas. We then extended these studies to primary human mesenchymal stem cells (hMSCs) isolated from bone marrow. Upon genetic modification with a lentiviral vector encoding PAX3, hMSCs activated the myogenic program as demonstrated by expression of myogenic regulatory factors. Upon transplantation, the PAX3-modified MSCs did not generate rhabdomyosarcomas but rather, resulted in donor-derived myofibers. These were found at higher frequency in PAX3-transduced hMSCs than in mock-transduced MSCs. Nonetheless, neither engraftment of PAX3-modified or unmodified MSCs resulted in improved contractility. Thus these findings suggest that limitations remain to be overcome before MSC preparations result in effective treatment for muscular dystrophies.
doi_str_mv 10.1016/j.yexcr.2009.05.009
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subjects Animals
Antigens, CD - metabolism
Biomarkers - metabolism
Cell Differentiation - physiology
Cells, Cultured
Dystrophin
Dystrophin - genetics
Dystrophin - metabolism
Genetic engineering
Humans
Male
Mesenchymal Stem Cell Transplantation
Mesenchymal stem cells
Mesenchymal Stromal Cells - cytology
Mesenchymal Stromal Cells - physiology
Mice
Mice, Knockout
Muscle Development - physiology
Muscle differentiation
Muscle, Skeletal - pathology
Muscle, Skeletal - physiology
Muscular Dystrophies - genetics
Muscular Dystrophies - pathology
Muscular Dystrophies - therapy
Muscular dystrophy
Neuregulin-1 - metabolism
Paired Box Transcription Factors - genetics
Paired Box Transcription Factors - metabolism
Pax3
PAX3 Transcription Factor
Recovery of Function
Rhabdomyosarcoma - metabolism
Rhabdomyosarcoma - pathology
Rodents
Side effects
Stem cells
Transplantation
Tumors
title Engraftment of mesenchymal stem cells into dystrophin-deficient mice is not accompanied by functional recovery
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