Contribution of minced muscle graft progenitor cells to muscle fiber formation after volumetric muscle loss injury in wild‐type and immune deficient mice

Abstract

Volumetric muscle injury (VML) causes an irrecoverable loss of muscle fibers, persistent strength deficits, and chronic disability. A crucial challenge to VML injury and possible regeneration is the removal of all of the in situ native elements necessary for skeletal muscle regeneration. Our first goal was to establish a reliable VML model in the mouse tibialis anterior (TA) muscle. In adult male wild‐type and nude mice, a non‐repaired ≈20% VML injury to the TA muscle resulted in an ≈59% loss in nerve evoked muscle strength, ≈33% loss in muscle mass, and ≈29% loss of muscle fibers at 28 day post‐injury. Our second goal was to investigate if minced muscle grafts (≈1 mm3 tissue fragments) promote recovery of muscle fibers after VML injury and to understand if the graft‐derived progenitor cells directly contribute to fiber regeneration. To assess donor cell contribution, donor muscle tissue was derived from UBC‐GFP mice in a subset of experiments. Minced grafts restored ≈34% of the lost fibers 28 days post‐injury. The number of GFP + fibers and the estimated number of regenerated fibers were similar, regardless of host mouse strain. The muscle tissue regeneration promoted by minced grafts did not improve TA muscle strength at this time post‐injury. These findings demonstrate the direct contribution of minced muscle graft‐derived myogenic stem/progenitor cells to recovery of muscle fibers after VML injury and signify the utility of autologous myogenic stem cell therapies for this indication.

Co-delivery of a laminin-111 supplemented hyaluronic acid based hydrogel with minced muscle graft in the treatment of volumetric muscle loss injury

“…This response, however, was not found to be significantly different from either the 50% MG + HA group or our previously published benchmark for the delivery of 50% MG without accompanying scaffolding [ 13 ] suggesting neither the HA in isolation or the in combination with laminin-111 contributed significantly to whole muscle function beyond the effects of the supplied MG material. Moreover, while graft-mediated de novo muscle fiber regeneration was indicated by the presence of GFP + muscle fibers, as demonstrated previously [ 13 , 15 , 40 ], the robustness of the regenerative response was qualitatively in line with a recent observation of tissue equivalent (50% MG-only) implantation and was clearly lesser than a 100% MG repair [ 13 ].…”

“…GFP was detected in the defect region of the 50% MG + HA+LMN treated muscles at both 2 and 8 weeks post-injury indicating survival of the graft derived progenitor cells and their involvement in the myofiber regeneration ( Fig 5 ). Qualitative observation of GFP + staining indicated that the majority of the regenerated myofibers within the defect region were minced graft derived, as observed previously with minced graft-only repair [ 13 , 15 , 40 ].…”

Autologous minced muscle grafts improve endogenous fracture healing and muscle strength after musculoskeletal trauma

“…; Corona et al. ), it is difficult to rationalize that a relatively small loss of the TA muscle (~20%) in the current study ablates such a large portion of the satellite cell pool that cannot be compensated for by the bulk of the surrounding musculature (e.g., triceps surae muscles) that is left intact. Therefore, specific characteristics of this open fracture model points toward immune and autocrine/paracrine responses in nonrepaired and minced graft‐repaired VML injured muscles as potential primary mediators of fracture healing.…”

Co-delivery of micronized urinary bladder matrix damps regenerative capacity of minced muscle grafts in the treatment of volumetric muscle loss injuries

“…Mincing of the autologous tissue causes the adult fibers to die but delivers viable muscle progenitors and basal lamina required for de novo skeletal muscle regeneration [ 24 , 25 ] and induces a canonical muscle injury response that promotes fiber regeneration [ 26 ]. Devitalization and donor cell-labeling experiments indicate that minced grafts deliver muscle progenitors (e.g., satellite cells) that directly contribute to skeletal muscle fiber regeneration [ 19 , 27 – 29 ]. A significant shortcoming of the use of autologous muscle tissue is the obligatory donor tissue burden for the repair of clinically large VML defects.…”