TY - JOUR

T1 - Characterization of DLK1+ cells emerging during skeletal muscle remodeling in response to myositis, myopathies, and acute injury

AU - Andersen, Ditte C.

AU - Petersson, Stine J.

AU - Jørgensen, Louise H.

AU - Bollen, Peter

AU - Jensen, Pernille B.

AU - Teisner, Børge

AU - Schroeder, Henrik D.

AU - Jensen, Charlotte H.

PY - 2009

Y1 - 2009

N2 - Delta like 1 (DLK1) has been proposed to act as a regulator of cell fate determination and is linked to the development of various tissues including skeletal muscle. Herein we further investigated DLK1 expression during skeletal muscle remodeling. Although practically absent in normal adult muscle, DLK1 was upregulated in all human myopathies analyzed, including Duchenne- and Becker muscular dystrophies. Substantial numbers of DLK11 satellite cells were observed in normal neonatal and Duchenne muscle, and furthermore, myogenic DLK11 cells were identified during muscle regeneration in animal models in which the peak expression of Dlk1 mRNA and protein coincided with that of myoblast differentiation and fusion. In addition to perivascular DLK11 cells, interstitial DLK11 cells were numerous in regenerating muscle, and in agreement with colocalization studies of DLK1 and CD90/DDR2, qPCR of fluorescence- activated cell sorting DLK11 and DLK12 cells revealed that the majority of DLK11 cells isolated at day 7 of regeneration had a fibroblast-like phenotype. The existence of different DLK11 populations was confirmed in cultures of primary derived myogenic cells, in which large flat nonmyogenic DLK11 cells and small spindle-shaped cells coexpressing DLK1 and muscle-specific markers were observed. Myogenic differentiation was achieved when sorted DLK11 cells were cocultured together with primary myoblasts revealing a myogenic potential that was 10% of the DLK12 population. Transplantation of DLK11 cells into lacerated muscle did, however, not give rise to DLK11 cell-derived myofibers. We suggest that the DLK11 subpopulations identified herein each may contribute at different levels/time points to the processes involved in muscle development and remodeling.

AB - Delta like 1 (DLK1) has been proposed to act as a regulator of cell fate determination and is linked to the development of various tissues including skeletal muscle. Herein we further investigated DLK1 expression during skeletal muscle remodeling. Although practically absent in normal adult muscle, DLK1 was upregulated in all human myopathies analyzed, including Duchenne- and Becker muscular dystrophies. Substantial numbers of DLK11 satellite cells were observed in normal neonatal and Duchenne muscle, and furthermore, myogenic DLK11 cells were identified during muscle regeneration in animal models in which the peak expression of Dlk1 mRNA and protein coincided with that of myoblast differentiation and fusion. In addition to perivascular DLK11 cells, interstitial DLK11 cells were numerous in regenerating muscle, and in agreement with colocalization studies of DLK1 and CD90/DDR2, qPCR of fluorescence- activated cell sorting DLK11 and DLK12 cells revealed that the majority of DLK11 cells isolated at day 7 of regeneration had a fibroblast-like phenotype. The existence of different DLK11 populations was confirmed in cultures of primary derived myogenic cells, in which large flat nonmyogenic DLK11 cells and small spindle-shaped cells coexpressing DLK1 and muscle-specific markers were observed. Myogenic differentiation was achieved when sorted DLK11 cells were cocultured together with primary myoblasts revealing a myogenic potential that was 10% of the DLK12 population. Transplantation of DLK11 cells into lacerated muscle did, however, not give rise to DLK11 cell-derived myofibers. We suggest that the DLK11 subpopulations identified herein each may contribute at different levels/time points to the processes involved in muscle development and remodeling.

KW - DLK1/PREF-1/FA1

KW - Fibroblasts

KW - Muscular diseases

KW - Progenitor cells

KW - Regeneration

KW - Skeletal muscle satellite cells

U2 - 10.1634/stemcells.2008-0826

DO - 10.1634/stemcells.2008-0826

M3 - Journal article

C2 - 19353518

AN - SCOPUS:65649117643

VL - 27

SP - 898

EP - 908

JO - Stem Cells

JF - Stem Cells

SN - 1066-5099

IS - 4

ER -