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Pax7 is necessary and sufficient for the myogenic specification of CD45+:Sca1+ stem cells from injured muscle.

ABSTRACT: CD45(+):Sca1(+) adult stem cells isolated from uninjured muscle do not display any myogenic potential, whereas those isolated from regenerating muscle give rise to myoblasts expressing the paired-box transcription factor Pax7 and the bHLH factors Myf5 and MyoD. By contrast, CD45(+):Sca1(+) isolated from injured Pax7( -/-) muscle were incapable of forming myoblasts. Infection of CD45(+):Sca1(+) cells from uninjured muscle with retrovirus expressing Pax7 efficiently activated the myogenic program. The resulting myoblasts expressed Myf5 and MyoD and differentiated into myotubes that expressed myogenin and myosin heavy chain. Infection of CD45(-):Sca1(-) cells from Pax7( -/-) muscle similarly gave rise to myoblasts. Notably, infection of Pax7-deficient muscle with adenoviral Pax7 resulted in the de novo formation of regenerated myofibers. Taken together, these results indicate that Pax7 is necessary and sufficient to induce the myogenic specification of CD45(+) stem cells resident in adult skeletal muscle. Moreover, these experiments suggest that viral transduction of Pax7 is a potential therapeutic approach for the treatment of neuromuscular degenerative diseases.

SUBMITTER: Seale P

PROVIDER: S-EPMC406392 | biostudies-literature | 2004 May

REPOSITORIES: biostudies-literature

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Pax7 is necessary and sufficient for the myogenic specification of CD45+:Sca1+ stem cells from injured muscle.

Seale Patrick P Ishibashi Jeff J Scimè Anthony A Rudnicki Michael A MA

PLoS biology 20040511 5

CD45(+):Sca1(+) adult stem cells isolated from uninjured muscle do not display any myogenic potential, whereas those isolated from regenerating muscle give rise to myoblasts expressing the paired-box transcription factor Pax7 and the bHLH factors Myf5 and MyoD. By contrast, CD45(+):Sca1(+) isolated from injured Pax7( -/-) muscle were incapable of forming myoblasts. Infection of CD45(+):Sca1(+) cells from uninjured muscle with retrovirus expressing Pax7 efficiently activated the myogenic program. ...[more]

PMID: 15138500

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Project description:Multipotent adult resident cardiac stem cells (CSCs) were first identified by the expression of c-kit, the stem cell factor receptor. However, in the adult myocardium c-kit alone cannot distinguish CSCs from other c-kit-expressing (c-kitpos) cells. The adult heart indeed contains a heterogeneous mixture of c-kitpos cells, mainly composed of mast and endothelial/progenitor cells. This heterogeneity of cardiac c-kitpos cells has generated confusion and controversy about the existence and role of CSCs in the adult heart. Here, to unravel CSC identity within the heterogeneous c-kit-expressing cardiac cell population, c-kitpos cardiac cells were separated through CD45-positive or -negative sorting followed by c-kitpos sorting. The blood/endothelial lineage-committed (Lineagepos) CD45posc-kitpos cardiac cells were compared to CD45neg(Lineageneg/Linneg) c-kitpos cardiac cells for stemness and myogenic properties in vitro and in vivo. The majority (~90%) of the resident c-kitpos cardiac cells are blood/endothelial lineage-committed CD45posCD31posc-kitpos cells. In contrast, the LinnegCD45negc-kitpos cardiac cell cohort, which represents ?10% of the total c-kitpos cells, contain all the cardiac cells with the properties of adult multipotent CSCs. These characteristics are absent from the c-kitneg and the blood/endothelial lineage-committed c-kitpos cardiac cells. Single Linnegc-kitpos cell-derived clones, which represent only 1-2% of total c-kitpos myocardial cells, when stimulated with TGF-?/Wnt molecules, acquire full transcriptome and protein expression, sarcomere organisation, spontaneous contraction and electrophysiological properties of differentiated cardiomyocytes (CMs). Genetically tagged cloned progeny of one Linnegc-kitpos cell when injected into the infarcted myocardium, results in significant regeneration of new CMs, arterioles and capillaries, derived from the injected cells. The CSC's myogenic regenerative capacity is dependent on commitment to the CM lineage through activation of the SMAD2 pathway. Such regeneration was not apparent when blood/endothelial lineage-committed c-kitpos cardiac cells were injected. Thus, among the cardiac c-kitpos cell cohort only a very small fraction has the phenotype and the differentiation/regenerative potential characteristics of true multipotent CSCs.

Dataset Information

Pax7 is necessary and sufficient for the myogenic specification of CD45+:Sca1+ stem cells from injured muscle.

Publications

Pax7 is necessary and sufficient for the myogenic specification of CD45+:Sca1+ stem cells from injured muscle.

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