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SATELLITE CELLS AND THE MUSCLE STEM CELL NICHE Hang Yin, Feodor Price, and Michael A. Rudnicki

  The complex behavior of satellite cells during skeletal muscle regeneration is tightly regulated through the dynamic interplay between intrinsic factors withinsatellite cells and extrinsic factors constituting the muscle stem cell niche/microenvironment. Here, we concentrate on the functions of satellite cells and the regulation of their niche during the process of skeletalmuscle regeneration.


  The direct juxtaposition of satellite cells and myofibers im- mediately raised a hypothesis that these cells may be in-volved in skeletal muscle growth and regeneration (329). In search of this mitogen, it was found that theproliferation and differentiation of satellite cell-derived myoblasts cultured in vitro respond to various growth fac-tors in a dose-dependent manner (10, 11).

3 H]thymidine labeling and elec-

3 H]thy-

  A recent study discovered a small subpopu-lation of satellite cells, characterized by their surface mark- ers Sca-1 " " CreER /!7-intergin # /Sca-1 # /CD31 # /CD11b # satellite cells tend to be associated with skeletal muscle of certain anatomicallocations (e.g., diaphragm and truck muscles), the differ- ence of Pax3 expression does not seem to correlate withtheir embryonic origins, metabolic fiber types, or types of innervating motor neurons. Notably,the heterogeneity of gene expression in single satellite cells was investigated in a recent study, wherein the expression ofPax7, Pax3, Myf5, and MyoD was interrogated by RT- qPCR for 40 individually FACS-isolated muscle stem cells(CD45 " Satellite cells were considered to be a homogeneous popu- lation of committed muscle progenitors (52).

C. Heterogeneity of Satellite Cell Population

  Remarkably, these two distinct satellite cell subpopulations also differ in terms of their regen-erative potential: the Pax7 " /YFP # satellite cells were able to reconstitute the stem cell niche and repaired muscles in a sus-tainable manner, whereas the Pax7 " SATELLITE CELLS AND THE MUSCLE STEM CELL NICHE # Pax7CreER YIN, PRICE, AND RUDNICKI Early experiments using a quail-chick chimera technique suggested a somitic origin of satellite cells in amniotes (18). Despite the plasticity of satellite cells in vitro, it is important to note that myogenesis is the predom-inant fate of satellite cells in vivo as fibrosis or adipose infiltra- tion is not normally observed in young healthy muscle.

D. Variance of Satellite Cells Number and Location

  " embryonic progenitor cells are the major source of adult satellite cells in truck and limb muscles; it is, however, note-worthy that the aforementioned observations from lineage tracing and immunofluorescence labeling experiments can-not exclude the possibility that some adult satellite cells may originate from other sources during fetal and postnatalmuscle development. During EMT, tightly packed epithelial cells tease apart and turn in a loose mes-enchymal state prior to assuming different developmental fates: cells in the medial dermomyotome will develop intobrown fat, dermis, and trunk muscle, while cells in the lateral dermomyotome will give rise to endothelia and limbmuscles.

2. Alternative origins of adult satellite cells

  It has beenreported that several types of nonsatellite cells can undergo Muscle regeneration occurs in three sequential but overlap- myogenic differentiation and contribute to muscle regenera- ping stages: 1) the inflammatory response; 2) the activation,tion after transplantation into regenerating muscle (24, 210, differentiation, and fusion of satellite cells; and 3) the mat- 287, 345, 413). Nevertheless, the contribution of these cells to uration and remodeling of newly formed muscle regeneration seems to be negligible compared with satellite cells, implying the physiological relevance of Muscle degeneration begins with necrosis of damaged mus-nonsatellite cell-based myogenesis might depend on Pax7 ex- cle fibers.

3 H]thymi-

  Asymmetric di- vision predominantly happens when the mitotic spindle isperpendicular to the myofiber axis (apical-basal division) with the satellite stem cell (Pax7 " " " ) and one satellite myogenic (Pax7 # /Myf5 " satellite cells, which give rise to one satellite stem cell (Pax7 # /Myf5 " /Myf5 satellite myogenic cell adjacent to the myofiber plasma membrane(apical). However, only Pax7 # #/# When both satellite stem cells and satellite myogenic cells are freshly sorted and transplanted into Pax7 satellite cells and in either case the mitotic spindle was frequently parallel to the myofiber axis (planardivision) and both daughter cells were in contact with the myofiber plasma membrane and the basal lamina.

D. Contributions and Therapeutic Potential of Nonsatellite Cells in Trauma-Induced Muscle Regeneration

1. Bone marrow stem cells

  These SP cells that reside in the satellite cell compartment, termed satellite-SP cells, are characterized by CD45 " and reside in the skeletal muscle interstitium juxtaposed to blood vessels, which make themdistinct from satellite cells and bone marrow-derived SP cells (24, 146, 210, 439, 464). Notably, muscle SP cells (Sca-1 2) PICs and FAPs represent the same cell population but in cells; or more likely " cells and thus the myogenic potential resides in these CD31 1) FAPs are depleted of CD31" Coculture with myogenic cells cannot promote the myo- genic potential of FAPs (252).

3. PW1

  In transgenic mice with a dominant nega- tive form of PW1 ($PW1) driven by a Myogenin promoter,embryonic and fetal muscle development is normal but post- natal muscle growth is severely impaired with a profound phe-notype, to some extent, reminiscent to that of Pax7 #/# germ- line mutant mice (376, 478). In con-trast, the number of Pax7 # /PW1 " interstitial cells (PIC) is significantly increased within postnatal muscles from Pax7#/# " # PICs give rise to both interstitial cells and Pax7 /CD45 " /CD34 # satellite cells, whereas Sca-1 " # satellite cells (345, 380, 478).

5. Mesoangioblasts

  Intriguingly, cells carrying the same surface marks can be isolated fromvarious tissues, including pancreas, adipose, and pla- centa and differentiate into skeletal muscle cells whencultured in vitro, irrespective of their origins (118). The fact that pericytes also display cell surface markers char-acteristic of mesenchymal stem cells (CD10 " " /CD144 /CD44 " /CD73 " /CD90 " ) raised the hypothesis that peri- cytes may represent a significant portion of mesenchymalstem cells in the adult (85, 118, 163).

7. CD133

  In addition, conditional expres- sion of Pax7 in human iPS cells was successful in inducinglarge quantities of myogenic progenitors, which were able to efficiently engraft and produce abundant human-deriveddystrophin " myofibers in dystrophic mouse muscle (123). A small subpopulation of CD133 / CD34 Recent studies demonstrated that a fraction of CD133 " double positive cells can be identified in the blood and skeletal muscle interstitium (233).

E. Satellite Cells in Perinatal/Juvenile Muscle Growth

  In neonatal mouse muscle, satellite cells account for !30 – 35% of the sublaminal nuclei on myofibers (9, 227, 471). This proportion of satellite cells decreases while the number of myonuclei increases over postnatal growth (150).

3 H]thymidine labeling indicate that satellite cells

  Similar to these adult stem cells, satellite cells arealso present in a highly specified niche, which consists of the extracellular matrix (ECM), vascular and neural networks,different types of surrounding cells, and various diffusible molecules (FIGURE 3) . Understanding the interactions between satellite cells and their niche is ofparamount importance for the development of therapies to treat both age-related skeletal muscle atrophy (sarcopenia)and skeletal muscle diseases.

3 H]thymidine labeling, two sub-

  In support of this hypothesis, genetically marked hemato- poietic stem cells (bone marrow derived CD45 # Despite their similarities, studies have revealed distinct ge- netic requirements for both juvenile and adult satellite cellpopulations. Pax7 is required for the maintenance of a func- tional myogenic cell population in the perinatal/juvenilestage, as muscle growth and regeneration are severely im- paired in Pax7 germline null mutants during this period(279, 393, 478). This observation suggests that 1) the majority of fast-cycling satellite cells only undergo a limitednumber of mitotic divisions prior to fusion, and 2) the num- ber of fast-cycling satellite cells in growing muscle are main-tained by the slow-cycling satellite cells through asymmetric divisions (471).

3 H]thymidine during a second 5-day

  Thus it is enticing to further spec- ulate that the activated Wnt/$-catenin pathway in regener-ating myofibers may induce Wnt7a secretion and activation of the Wnt/PCP pathway in adjacent satellite stem cells,which in turn would direct their symmetric division and replenish the satellite cell pool. Theactivation of Notch signaling pathway is initiated by the binding of Delta and Jagged family of ligands to Notchtransmembrane receptors, the result of which induces se- quential enzymatic cleavage of the Notch receptor and re-lease of an active truncated form of Notch, termed theNotch intracellular domain (NICD).


  Interestingly, the spontaneous myogenic differentia- tion of the majority of mutant satellite cells in this modelseems to start with G (quiescent) satellite cells without entry into S phase in vivo. This action of S1P on satellite cell activationand muscle regeneration is in line with the proliferative, proinflammatory (through COX-2) and antiapoptotic(through inhibition of caspase-3 and BAX) functions ofS1P-mediated pathways in general.

C) SPHINGOLIPID SIGNALING . Sphingolipids are a large group

  Upon injury, the transcription of HGF is increased in pro- portion to the degree of injury, and an active form of HGFis released from the ECM without the need of proteolytic cleavage of pro-HGF (484, 520, 521, 525, 569). The activation of satel-lite cells by HGF is due to both transcription activation ofHGF in satellite cells and release of HGF from the ECM byMMPs, which coordinately function in an autocrine and paracrine fashion to induce the proliferation of satellitecells.

3. ECM and associated factors


  In contrast to IGF-I-induced musclehypertrophy, IGF1R IGF can function in endocrine, autocrine, and paracrine fashions to promote satellite cell proliferation and differen-tiation, but all of these are mediated by IGF-I binding to the mutant mice are !40% lighter compared with the weight of wild-type mice at birth, andthis defect persists postnatally (133). # mutant mice revealed severe muscle re- generation defects characterized by a reduction in MyoD YIN, PRICE, AND RUDNICKI Activated satellite cells and cultured myoblasts express in- sulin-like growth factor binding proteins (IGFBPs), whichare a family of secreted proteins that specifically bind IGFs and function as carriers during circulation and regulate IGF turnover, transport, and half-life (reviewed in Ref.253).


  Re- cent observations regarding the effect of fibrosis on thestiffness of the ECM raise the question as to whether in- creased depositions from fibroblasts or adipocytes can altermyofiber stiffness and therefore affect the physiological roles attributed to satellite cells (152; discussed in sect. Once homeostasis of muscle is achieved, the proximity of satellite cells and periendothelial cells permits angiopoi-etin-1, which is secreted by periendothelial cells, to bindTie-2 receptors on satellite cells to simultaneously stabilize vessels and promote satellite cell quiescence (4, 100).

2. Systemic milieu


  Furthermore, it was shown that the proliferation of sat- ellite cells from IL-6 #/# mice was impaired both in vivo and in vitro, which is due to the attenuation of STAT3signaling (480). 1) maintaining a sustainable reservoir of stem cells, 2) pro- Compelling evidence indicates that adult satellite cells rep- resent a heterogeneous population of stem cells and com-mitted myogenic progenitors in skeletal muscle.

D) NITRIC OXIDE . NO is a diffusible small molecule, which can

  Loss of nNOS from the sarco-lemma (e.g., as a result of a dystrophin deficiency) leads to inflammation and myofiber lysis, implicating a protectivefunction for NO in skeletal muscle (89). If so, the broad interest of future studies should focus on identification of the intrinsic andextrinsic regulatory mechanisms that govern satellite cell commitment and differentiation throughout the muscle re-generation.

G. PW1 gene/paternally expressed gene 3 (PW1/Peg3) identifies multiple adult stem and progenitor cell populations. Proc Natl Acad Sci USA 108: 11470 –11475, 2011

  Satellite cell proliferation and increase in the number of myonuclei induced by testosterone in the levator ani muscle of the adult female rat. Skeletal muscle cells lacking the retino- blastoma protein display defects in muscle gene expression and accumulate in S andG 2 phases of the cell cycle.

F. Mutations in the caveolin-3 gene cause autosomal dominant limb-girdle muscular dystrophy. Nat Genet 18: 365–368, 1998

  Satellite cell proliferation and the expression of myogenin and desmin in regenerating skeletal muscle: evidence for twodifferent populations of satellite cells. Expression of functional CXCR4 by muscle satellite cells and secretionof SDF-1 by muscle-derived fibroblasts is associated with the presence of both muscle progenitors in bone marrow and hematopoietic stem/progenitor cells in muscles.

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