Characterization of DLK1+ Cells Emerging During Skeletal Muscle Remodeling in Response to Myositis, Myopathies, and Acute Injury

Abstract

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 DLK1 1 satellite cells were observed in normal neonatal and Duchenne muscle, and furthermore, myogenic DLK1 1 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 DLK1 1 cells were numerous in regenerating muscle, and in agreement with colocalization studies of DLK1 and CD90/DDR2, qPCR of fluorescence-activated cell sorting DLK1 1 and DLK1 2 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 DLK1 2 population. Transplantation of DLK1 1 cells into lacerated muscle did, however, not give rise to DLK1 1 cell-derived myofibers. We suggest that the DLK1 1 subpopulations identified herein each may contribute at different levels/time points to the processes involved in muscle development and remodeling. STEM CELLS 2009;27:898-908 Disclosure of potential conflicts of interest is found at the end of this article.

DLK1/PREF1 regulates nutrient metabolism and protects from steatosis

“…We used a BAC transgenic model containing the Dlk1 gene within 70 kb of the surrounding sequence and generated three independent transgenic lines (70A, 70B, and 70C) (18). Postnatally, Dlk1 is expressed in the adrenal gland (23), the somatotrophs of the pituitary (24), in a small number of cells in the brain (25), and in stromal-vascular cell populations associated with muscle and adipose tissues (11,26,27). Dlk1-transgenic hemizygous animals (WT/TG) recapitulated this postnatal restriction of Dlk1 expression, ( Fig.…”

Activation of paternally expressed genes and perinatal death caused by deletion of theGtl2gene

“…Dlk1 has been implicated in skeletal muscle development. It is involved in differentiation of skeletal stem cells (Abdallah et al, 2004) and skeletal muscle remodeling (Andersen et al, 2009). Davis et al (Davis et al, 2004) reported that overexpression of Dlk1 resulted in skeletal muscle hypertrophy.…”

Development of Novel Monoclonal Antibodies that Define Differentiation Stages of Human Stromal (Mesenchymal) Stem Cells

“…Additionally, we used tissue array blocks comprising a panel of normal and abnormal fetal and adult human tissues (kindly provided by Henrik Daa Schrøder, Department of Pathology, Odense University Hospital, Denmark) for further testing of DJ 3, 9, and 18. Immunohistochemical staining was performed as described previously (Andersen et al, 2009), including block of endogenous peroxidase activity and antigen demasking by boiling in TEG buffer [10 mM Tris (SIGMA T-1378)/0.5 mM EGTA (Merck 8435), pH 9.0]. In case of tissue arrays IHC, we blocked endogenous biotin using a biotin-avidin kit system (DAKO A/S, DK), and TEG demasking was performed at 60°C for 24 h to prevent damage of tissues enriched for collagens.…”