Biomaterial and stem cell‐based strategies for skeletal muscle regeneration

Abstract

Adult skeletal muscle can regenerate effectively after mild physical or chemical insult. Muscle trauma or disease can overwhelm this innate capacity for regeneration and result in heightened inflammation and fibrotic tissue deposition resulting in loss of structure and function. Recent studies have focused on biomaterial and stem cell‐based therapies to promote skeletal muscle regeneration following injury and disease. Many stem cell populations besides satellite cells are implicated in muscle regeneration. These stem cells include but are not limited to mesenchymal stem cells, adipose‐derived stem cells, hematopoietic stem cells, pericytes, fibroadipogenic progenitors, side population cells, and CD133+ stem cells. However, several challenges associated with their isolation, availability, delivery, survival, engraftment, and differentiation have been reported in recent studies. While acellular scaffolds offer a relatively safe and potentially off‐the‐shelf solution to cell‐based therapies, they are often unable to stimulate host cell migration and activity to a level that would result in clinically meaningful regeneration of traumatized muscle. Combining stem cells and biomaterials may offer a viable therapeutic strategy that may overcome the limitations associated with these therapies when they are used in isolation. In this article, we review the stem cell populations that can stimulate muscle regeneration in vitro and in vivo. We also discuss the regenerative potential of combination therapies that utilize both stem cell and biomaterials for the treatment of skeletal muscle injury and disease. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 37:1246–1262, 2019.

Decellularized extracellular matrix gelloids support mesenchymal stem cell growth and function in vitro

“…The DNA content was determined to be less than 50-ng/mg dry weight ( Figure 1a). Previous studies have shown that this range is acceptable for decellularized scaffolds (Crapo, Gilbert, & Badylak, 2011;Dunn et al, 2019;McClure et al, 2018). The D-ECM was subjected to SDS-polyacrylamide gel electrophoresis and western blotting to confirm the presence of collagen and laminin (data not shown).…”

“…However, D‐ECM scaffolds have failed to regenerate muscle at clinically relevant levels and often result in fibrotic tissue deposition (Aurora, Roe, Corona, & Walters, , Corona, Wu, et al, , Garg, Ward, & Corona, , Gentile et al, , Machingal et al, , Mase et al, ). A major limitation of D‐ECM scaffolds is their inability to stimulate endogenous cell migration and activity leading to incomplete muscle repair (Dunn et al, ). A possible way to overcome this problem is to combine D‐ECM scaffolds with an appropriate cell population, such as mesenchymal stem cells (MSCs).…”

“…Combining stem cell and biomaterial-based therapies may overcome several limitations and challenges associated with these therapies when used in isolation (Dunn et al, 2019). We hypothesized that aggregating MSCs on a spherical scaffold that provides key ECM components and allows for both cell-cell and cell-matrix interactions might overcome several drawbacks while maintaining the enhanced therapeutic potential of 3D MSC spheroids.…”

Biomimetic sponges improve muscle structure and function following volumetric muscle loss

“…The extracellular matrix (ECM) forms an ideal microenvironment for cell survival and activity. The ECM not only provides a framework for structural and mechanical support but also sequesters cytokines and growth factors to orchestrate cell migration, proliferation, and differentiation [9,10]. As a result, acellular ECM scaffolds have been extensively used for the treatment of skeletal muscle injuries.…”

Journal of Orthopaedic Research: Special Issue on Stem Cells

“…This Special Issue also contains several state‐of‐the‐art reviews on stem cells in orthopedics. Dunn et al review various biomaterial and stem cell‐based strategies for skeletal muscle regeneration, while Walia and Huang review the biology of tendon stem/progenitor cells as a basis for informing new therapeutic strategies for tendon repair. With the evolving concepts of MSCs in regenerative medicine, Barry provides an update of the long‐standing application of MSCs as a therapy for osteoarthritis and Guilak et al summarize the current state of the art in genome editing for the development of “designer” stem cells as the next generation of cell‐based therapies for musculoskeletal conditions.…”