Restoration of Skeletal Muscle Defects with Adult Human Cells Delivered on Fibrin Microthreads

Abstract

Large-scale musculoskeletal wounds, such as those seen in trauma injuries, present poor functional healing prognoses. In severe trauma, when the native tissue architecture is destroyed or lost, the regenerative capacity of skeletal muscle is diminished by scar formation. Here we demonstrate that a scaffold system composed of fibrin microthreads can provide an efficient delivery system for cell-based therapies and improve regeneration of a large defect in the tibialis anterior of the mouse. Cell-loaded fibrin microthread bundles implanted into a skeletal muscle resection reduced the overall fibroplasia-associated deposition of collagen in the wound bed and promoted in-growth of new muscle tissue. When fibrin microthreads were seeded with adult human cells, implanted cells contributed to the nascent host tissue architecture by forming skeletal muscle fibers, connective tissue, and PAX7-positive cells. Stable engraftment was observed at 10 weeks postimplant and was accompanied by reduced levels of collagen deposition. Taken together, these data support the design and development of a platform for microthread-based delivery of autologous cells that, when coupled to an in vitro cellular reprogramming process, has the potential to improve healing outcomes in large skeletal muscle wounds.

Trends in Mesenchymal Stem Cells' Applications for Skeletal Muscle Repair and Regeneration

“…Skeletal muscle SCs delivered to a regenerating muscle effectively contribute to the replenishment of the resident satellite pool, migrating to locations far from the lesion site within the muscle. These freshly isolated native skeletal muscle stem cells contribute in high extents to the total Pax7 + population (about 38%), unlike expanded MPCs, that only account for about as little as 12% [35], but can still be identified within the muscle tissue and in association to connective structures [31]. Nonmuscular sources seem to behave closer to MPCs in terms of niche replenishment.…”

“…However, nonmuscular MSCs depict hardly any spontaneous tendency toward myodifferentiation (0.001%) [6], unlike the "MSC-like" populations residing in the muscle tissue that show a degree of lineage commitment to myogenic formation, undergoing spontaneous differentiation in standard culture [31]. Not all MSC sources seem to show the same tendency or predisposition toward this differentiation pathway upon stimuli.…”

“…This stage is highly significant for the outcome of the whole process and fine regulation of the late fibrotic events turns essential [28][29][30]. Especially after severe tissue loss, the fibrin matrix derived from the clotting process and inflammatory response requires remodeling into collagen type 1 network, produced by fibroblastic cells [31]. The development of definitive fibrosis at a lesion site begins at approximately 2 weeks after injury and progresses over time.…”

“…Despite of their demonstrated benefits in several settings [38], the practical use of postnatal skeletal muscle progenitors or SCs is limited due to decreased cell availability (requiring the harvest of large volumes of healthy tissue for adequate numbers) [31,39]. The expansion of MDSCs is possible, but as it has long been known, it leads to dedifferentiation of early committed myogenic cells [40] and loss of potential.…”

Evaluation of adipose-derived stem cells for tissue-engineered muscle repair construct-mediated repair of a murine model of volumetric muscle loss injury

“…24,25 Stem cells offer an attractive alternative. To date, a host of stem cell types have been evaluated in muscle repair applications, including embryonic stem cells, 13,26 pluripotent adult stem cells, 22,27 muscle resident side population cells, 14 bone marrow-derived stem cells, 20,22 stromal cells isolated from synovial membrane, 21 human umbilical cord-derived cells, 28 pericytes, 15 and meso-angioblasts. 29 In this study, we evaluated the potential of adiposederived stem cells (ADSCs) as an alternative cell source for tissue-engineered skeletal muscle to circumvent the limited scaling ability of MDCs.…”