Mesenchymal Stromal Cell Transplantation Ameliorates Fibrosis and Dysregulated microRNA Signature Associated with Ischaemic Skeletal Muscle Damage.

Peripheral arterial disease (PAD) is strongly associated with lower-extremity muscle wasting. Hallmark features of PAD associated skeletal muscle pathology include a loss of skeletal muscle mass, reduced strength and physical performance, as well as increased inflammation, fibrosis and adipocyte infiltration, among others. At a molecular level, skeletal muscle ischaemia has also been associated with gene and microRNA (miRNA) dysregulation. Mesenchymal stromal cells (MSCs) have been previously reported to enhance muscle regeneration and improve muscle function in a variety of skeletal muscle injuries. The aim of this study was to evaluate the effects of intramuscularly delivered human umbilical cord-derived MSCs (hUC-MSCs) on skeletal muscle regeneration in a preclinical model of acute skeletal muscle ischaemia. Herein, we report an hUC-MSC-mediated amelioration of ischaemia-induced skeletal muscle atrophy and function via enhancement of myofibre regeneration, reduction of tissue inflammation, adipocyte accumulation, and tissue fibrosis. These changes were observed in the absence of a cell-mediated enhancement of blood flow recovery measured by laser doppler imaging. Furthermore, the reduced tissue fibrosis in the cell-treated group was associated with an upregulation of miR-1, miR-133a and miR-29b and downregulation of targeted pro-fibrotic genes such as Col1a1 and Fn1. Our results support the use of hUC-MSC as a potential novel approach to reduce fibrosis and promote skeletal muscle regeneration after ischaemic injury in patients with PAD.