Optimization of a pericyte therapy to improve muscle recovery after limb immobilization

Abstract

Extended bed rest or limb immobilization can significantly reduce skeletal muscle mass and function. Recovery may be incomplete, particularly in older adults. Our laboratory recently reported that vascular mural cell (pericyte) quantity is compromised after immobilization and appropriate replacement immediately prior to remobilization can effectively recover myofiber size in mice. Identification of a single cell surface marker for isolation of the most therapeutic pericyte would streamline efforts to optimize muscle recovery. The purpose of this study was to compare the capacity for neural/glial antigen 2 (Cspg4/NG2+) and melanoma cell adhesion molecule (Mcam/CD146+) positive pericytes to uniquely recover skeletal muscle post-disuse. A single hindlimb from adult C57BL/6J mice was immobilized in full dorsiflexion via a surgical staple inserted through the center of the foot and body of the gastrocnemius. Fourteen days after immobilization, the staple was removed and pericytes, either NG2+CD45-CD31-[Lin-], CD146+NG2-Lin-, or CD146+Lin- pericytes, were injected into the atrophied tibialis anterior muscle. TA muscles were excised 14 days after transplantation and remobilization. Pericyte transplantation did not significantly improve muscle mass or myofiber CSA after 14 days of remobilization. However, injection of CD146+ pericytes significantly increased Type IIa quantity, capillarization and collagen remodeling compared to NG2+ pericytes (p<0.05). Our results suggest that selection of pericytes based on CD146 rather than NG2 results in the isolation of therapeutic mural cells with high capacity to positively remodel skeletal muscle after a period of immobilization.

Pericyte in retinal vascular diseases: A multifunctional regulator and potential therapeutic target

“…PCs vary in their treatment capacity. CD146 + PCs have a greater ability to recover Type IIa fiber quantity, capillary density, and collagen turnover after limb immobilization than NG2 + PCs 117 . Moreover, transplantation of human PCs can be used for heart repair.…”

“…CD146 + PCs have a greater ability to recover Type IIa fiber quantity, capillary density, and collagen turnover after limb immobilization than NG2 + PCs. 117 Moreover, transplantation of human PCs can be used for heart repair. Transplanting PC progenitor cells from saphenous vein into the peri-infarct zone of mice decreased myocardial scarring, cardiomyocyte death, interstitial fibrosis, pathological neovascularization, and improved vascular permeability.…”

MuSCs and IPCs: roles in skeletal muscle homeostasis, aging and injury

“…It was reported that disuse had marginal effects on gene expression in muscle pericytes, but the number of NG2 + Lin − pericytes decreased following immobilization [ 140 ]. A recent study found that CD146 + Lin − pericytes display a higher capacity to restore type IIa fibre count after disuse compared to NG2 + Lin − pericytes [ 141 ]. Intriguingly, CD146 + pericytes harbour the ability to secrete immune regulatory elements, drive angiogenesis and counteract fibrotic factors during skeletal muscle contraction, thereby actively reshaping the skeletal muscle [ 141 , 142 ].…”

“…A recent study found that CD146 + Lin − pericytes display a higher capacity to restore type IIa fibre count after disuse compared to NG2 + Lin − pericytes [ 141 ]. Intriguingly, CD146 + pericytes harbour the ability to secrete immune regulatory elements, drive angiogenesis and counteract fibrotic factors during skeletal muscle contraction, thereby actively reshaping the skeletal muscle [ 141 , 142 ]. The subpopulation of pericytes has also been implicated in the accumulation and infiltration of fat in diseased skeletal muscle, including conditions such as obesity, dystrophies, and aging (Fig.…”

Capillary-Mitochondrial Oxygen Transport in Muscle: Paradigm Shifts

“…Reminiscent of Krogh’s search for a mechanism by which individual capillaries might control their own hemodynamics, it has been claimed that pericytes exert a “canonical” role in regulating skeletal muscle vessel diameter. 206 However, some of the strongest evidence that pericytes can constrict/dilate capillaries comes from other tissues, most notably brain 207–210 and heart muscle. 211 , 212 ; rev.…”