Role of Pericytes in Skeletal Muscle Regeneration and Fat Accumulation

Abstract

Stem cells ensure tissue regeneration, while overgrowth of adipogenic cells may compromise organ recovery and impair function. In myopathies and muscle atrophy associated with aging, fat accumulation increases dysfunction, and after chronic injury, the process of fatty degeneration, in which muscle is replaced by white adipocytes, further compromises tissue function and environment. Some studies suggest that pericytes may contribute to muscle regeneration as well as fat formation. This work reports the presence of two pericyte subpopulations in the skeletal muscle and characterizes their specific roles. Skeletal muscle from Nestin-GFP/ NG2-DsRed mice show two types of pericytes, Nestin-GFP-/NG2-DsRed + (type-1) and Nestin-GFP + /NG2-DsRed + (type-2), in close proximity to endothelial cells. We also found that both Nestin-GFP-/NG2-DsRed + and Nestin-GFP + /NG2-DsRed + cells colocalize with staining of two pericyte markers, PDGFRb and CD146, but only type-1 pericyte express the adipogenic progenitor marker PDGFRa. Type-2 pericytes participate in muscle regeneration, while type-1 contribute to fat accumulation. Transplantation studies indicate that type-1 pericytes do not form muscle in vivo, but contribute to fat deposition in the skeletal muscle, while type-2 pericytes contribute only to the new muscle formation after injury, but not to the fat accumulation. Our results suggest that type-1 and type-2 pericytes contribute to successful muscle regeneration which results from a balance of myogenic and nonmyogenic cells activation.

Pericytes, mesenchymal stem cells and their contributions to tissue repair

“…In accordance with the ISCT definition of MSC, Crisan et al demonstrated that pericytes isolated from human skeletal muscle, pancreas, adipose tissue, placenta and bone marrow all express CD105, CD73 and CD90 as well as other known MSC markers, both in vivo and in long-term culture. In addition, these cells are plastic adherent and could undergo the classic MSC tri-lineage differentiation into bone, cartilage and fat (Crisan et al, 2008) as well as muscle (Birbrair et al, 2013a). Moreover, some studies have demonstrated that pericytes are also neural cell precursors (Birbrair et al, 2013b;Montiel-Eulefi et al, 2012).…”

“…Studies have shown that muscle-specific stem cells called satellite cells located between the basal lamina and sarcolemma of individual myofibres participate in skeletal muscle repair in response to injury, along with a range of other cells with myogenic potential, such as the muscle side population cells, ECs, interstitial cells and pericytes (Birbrair et al, 2013a). There is controversy as to the origins of satellite cells, and there are studies which suggest that they are completely distinct from pericytes and do not share any phenotypic or functional similarities (Caplan, 2008).…”

“…With regards to adipogenesis, Uezumi et al showed that PDGFRα+ MSCs, completely distinct from PDGFRβ+ pericytes, are responsible for adipogenesis in skeletal muscles and a balance between satellite cell-derived myofibres and PDGFRα+ cells maintain muscle homeostasis (Uezumi et al, 2010). However, differentiation of pericytes into adipocytes has been documented (Birbrair et al, 2013a;Farrington-Rock et al, 2004;Tang et al, 2008), and the differences between studies may well be dependent on the muscle condition and the subsequent interaction between cell types in the context of muscle injury.…”

“…Further studies investigating whether the absence of Type 2 pericytes may compromise skeletal muscle regeneration endogenously may be of use to advance therapies utilising pericytes for tissue repair (Birbrair et al, 2013a). Of note, the host microenvironment for cell therapy appears to be crucial as it has been shown that regenerative capacity of pericytes decreases when transplanted into older recipients (Birbrair et al, 2013d).…”

Molecular Regulation and Rejuvenation of Muscle Stem (Satellite) Cell Aging

“…(92) Aging is accompanied by a decline in neuromuscular performance, skeletal muscle mass and stem cell function. (176,177) Weakened muscles substantially increase the chance of injury, such as by falling. Because of the reduced regenerative capacity of aged tissues, recovery from such incidents and from subsequent surgical procedures is slow and possibly incomplete.…”