CD34 Promotes Satellite Cell Motility and Entry into Proliferation to Facilitate Efficient Skeletal Muscle Regeneration

Biomedical Research Centre, University of British Columbia, Vancouver, British Columbia, Canada.
Stem Cells (Impact Factor: 7.7). 12/2011; 29(12):2030-41. DOI: 10.1002/stem.759
Source: PubMed

ABSTRACT Expression of the cell surface sialomucin CD34 is common to many adult stem cell types, including muscle satellite cells. However, no clear stem cell or regeneration-related phenotype has ever been reported in mice lacking CD34, and its function on these cells remains poorly understood. Here, we assess the functional role of CD34 on satellite cell-mediated muscle regeneration. We show that Cd34(-/-) mice, which have no obvious developmental phenotype, display a defect in muscle regeneration when challenged with either acute or chronic muscle injury. This regenerative defect is caused by impaired entry into proliferation and delayed myogenic progression. Consistent with the reported antiadhesive function of CD34, knockout satellite cells also show decreased motility along their host myofiber. Altogether, our results identify a role for CD34 in the poorly understood early steps of satellite cell activation and provide the first evidence that beyond being a stem cell marker, CD34 may play an important function in modulating stem cell activity.

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    • "The most common way to assess endometriotic lesion vascular development is to evaluate microvessel density using endothelial cell specific markers such as CD31 (Machado et al., 2010), von willebrand factor (Becker et al., 2005; Capobianco et al., 2011) or factor VIII (Dabrosin et al., 2002) followed by quantitative morphometry analysis to determine the area of the tissue covered by blood vessels. Some studies have also used CD34 as a specific endothelial cell marker in mice (Olivares et al., 2011; Ricci et al., 2011), however this approach could be problematic as CD34 is expressed by hematopoietic progenitor cells (Krause et al., 1994) mature leukocytes (Drew et al., 2002), and satellite cells (Alfaro et al., 2011) in mice. Vascular development has also been indirectly assessed by looking at VEGF expression in response to anti-angiogenic compounds (Xu et al., 2012; Ricci et al., 2011). "
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    ABSTRACT: Endometriosis is a gynecological disease characterized by the growth of endometrium outside of the uterine cavity. It is often associated with dysmenorrhea, dyspareunia, pelvic pain and infertility. One of the key requirements for endometriotic lesions to survive is development of a blood supply to support their growth. Indeed, dense vascularization is characteristic feature of endometriotic lesions. This has led to the idea that suppression of blood vessel growth (anti-angiogenic therapy) may be a successful therapeutic approach for endometriosis. Potential effectiveness of anti-angiogenic therapies has been assessed in some animal models but there are no reports of human clinical trials. Without understanding the specific mechanism by which endometriosis lesions establish a new blood supply, short-term animal experiments will have limited value for translation into human medicine. Further, it is crucial to use appropriate animal models to assess efficacy of anti-angiogenic compounds. Syngeneic and autologous rodent models, where endometrial fragments are auto-transplanted into the peritoneal cavity are commonly used in anti-angiogenic therapy studies. Another approach is xenograft models where human endometrium is engrafted into immunodeficient mice. Here we review the animal models and experimental techniques used to evaluate anti-angiogenic therapies for endometriosis. We also review our own work on the role of stromal cell derived factor-1 in the recruitment of endothelial progenitor cells in endometriotic lesion angiogenesis, and the effects of the anti-angiogenic peptide ABT-898, a thrombospondin-1 mimetic, on endometriotic lesion growth and vascular development.
    Journal of Reproductive Immunology 03/2013; 97(1):85-94. DOI:10.1016/j.jri.2012.10.012 · 2.37 Impact Factor
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    • "CD34 is a cell surface protein marker found, among others, on satellite cells. It has recently been reported that CD34 promotes re-entry into the cell cycle after injury (Alfaro et al., 2011; Beauchamp et al., 2000), which is consistent with the phenotype induced by Yap. In this group, several genes were downregulated by hYAP1 S127A overexpression. "
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    ABSTRACT: Satellite cells are the resident adult stem cells of skeletal muscle. Mitotically quiescent in mature muscle, they can be activated to proliferate and generate myoblasts to supply further myonuclei to hypertrophying or regenerating muscle fibres, or self-renew to maintain the resident stem cell pool. Here, we identify the transcriptional co-factor Yap as a novel regulator of satellite cell fate decisions. Yap expression increases during satellite cell activation and Yap remains highly expressed until after the differentiation versus self-renewal decision is made. Constitutive expression of Yap maintains Pax7(+) and MyoD(+) satellite cells and satellite cell-derived myoblasts, promotes proliferation but prevents differentiation. In contrast, Yap knock down reduces the proliferation of satellite cell-derived myoblasts by ≈40%. Consistent with the cellular phenotype, microarrays show that Yap increases expression of genes associated with Yap inhibition, the cell cycle, ribosome biogenesis and that Yap represses several genes associated with angiotensin signalling. We also identify known regulators of satellite cell function such as BMP4, CD34 and Myf6 (Mrf4) as genes whose expression is dependent on Yap activity. Finally we confirm in myoblasts that Yap binds to Tead transcription factors and co-activates MCAT elements which are enriched in the proximal promoters of Yap-responsive genes.
    Journal of Cell Science 10/2012; 125(24). DOI:10.1242/jcs.109546 · 5.33 Impact Factor
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    ABSTRACT: Satellite cells (SCs) are essential for postnatal muscle growth and regeneration, however, their expansion potential in vitro is limited. Recently, hypoxia has been used to enhance proliferative abilities in vitro of various primary cultures. Here, by isolating SCs from single mouse hindlimb skeletal myofibers, we were able to distinguish two subpopulations of clonally cultured SCs (Low Proliferative Clones - LPC - and High Proliferative Clones - HPC), which, as shown in rat skeletal muscle, were present at a fixed proportion. In addition, culturing LPC and HPC at a low level of oxygen we observed a two fold increased proliferation both for LPC and HPC. LPC showed higher myogenic regulatory factor (MRF) expression than HPC, particularly under the hypoxic condition. Notably, a different myogenic potential between LPC and HPC was retained in vivo: green fluorescent protein (GFP)+LPC transplantation in cardiotoxin-injured Tibialis Anterior led to a higher number of new GFP+muscle fibers per transplanted cell than GFP+HPC. Interestingly, the in vivo myogenic potential of a single cell from an LPC is similar if cultured both in normoxia and hypoxia. Therefore, starting from a single satellite cell, hypoxia allows a larger expansion of LPC than normal O(2) conditions, obtaining a consistent amount of cells for transplantation, but maintaining their myogenic regeneration potential.
    PLoS ONE 11/2012; 7(11):e49860. DOI:10.1371/journal.pone.0049860 · 3.53 Impact Factor
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