Engineering Stem and Stromal Cell Therapies for Musculoskeletal Tissue Repair

Abstract

Stem cells and tissue-derived stromal cells stimulate the repair of degenerated and injured tissues, motivating a growing number of cell-based interventions in the musculoskeletal field. Recent investigations have indicated that these cells are critical for their trophic and immunomodulatory role in controlling endogenous cells. This Review presents recent clinical advances where stem cells and stromal cells have been used to stimulate musculoskeletal tissue repair, including delivery strategies to improve cell viability and retention. Emerging bioengineering strategies are highlighted, particularly toward the development of biomaterials for capturing aspects of the native tissue environment, altering the healing niche, and recruiting endogenous cells.

Keywords: biomaterials; clinical trials; mesenchymal stromal cells; musculoskeletal tissue repair; stem cells; tissue engineering.

Figure 1. Musculoskeletal tissues with high incidence of injuries and degeneration

The skeleton, joints, cartilage, intervertebral disc (IVD), tendons, ligaments and muscles are part of the musculoskeletal system, which provides stability and motion. Musculoskeletal diseases due to injuries and degeneration are one of the major causes of pain and disability. Cell therapies for musculoskeletal tissue repair are at different levels of evidence in clinical trials. For implantation of these cells, various delivery approaches are being used to optimize viability and minimize patient duress.

Figure 2. Advanced bioengineering concepts using biomaterials to control cell behavior (A)

The extracellular matrix of native connective tissue is highly dynamic and supports resident cells through presentation of biological and biophysical cues. (B) Biomaterials can recreate aspects of the tissue-specific microenvironment with biochemical signals to mimic cell-ECM and cell-cell interactions or to allow encapsulated cells to actively interact and integrate with their matrix environment. (C) Biomaterials can also be engineered to release chemo-attractive cytokines (e.g. stromal cell-derived factor 1α (SDF- 1α)) that enable migration of resident cells (e.g. mesenchymal stromal cells (MSCs)) or direct cell behavior by controlled release of encapsulated biological factors (e.g. bone-morphogenetic protein (BMP), transforming growth factor-β (TGF-β)). (D) Scaffold microenvironments are further being developed to alter the healing niche, for example by inducing a specific anti-inflammatory immune response or by releasing cytokines (e.g. interleukin 4 (IL-4) that activate M2 macrophages and promote tissue repair.

Figure 3. Examples of biomaterials engineered to recruit and control endogenous stem and stromal cell behavior in vivo (A)

Implantation of muscle satellite cells (MuSCs) in self-assembled nanofibers enhanced donor cell mediated repair of myofibers. Representative immunostaining of muscle tissue sections 5 weeks after implantation shows enhanced engraftment of GFP⁺ MuSCs compared with cells injected in buffer only. (B) Connective tissue growth factor (CTGF) released from fibrin hydrogels improved repair of transected rat patellar tendons. Gross images and representative histological images 4 weeks after implantation showed dense alignment of collagen fibers for fibrin gels with CTGF by stimulating proliferation and differentiation of endogenous tendon progenitor cells. (C) Bone-morphogenetic protein (BMP-2) incorporated into matrix metalloproteinases (MMP)-degradable hyaluronic acid (HA) hydrogels sustained release of BMP-2 through cell-mediated hydrogel degradation. Representative μ-CT images of rat calvarial defects 6 weeks after implantation demonstrate increased bone volume for faster degrading HA-hydrogels. (D) New bone tissue formation can also be increased through implantation of nanofibrous poly(l-lactic acid) (PLLA) microspheres that contain gelatin-heparin/BMP-2 microspheres (scanning electron microscope (SEM) image of a typical nanofibrous PLLA microsphere). Representative μ-CT images of rat calvarial defects 6 weeks after implantation show improved bone regeneration for PLLA microspheres with heparin-conjugated gelatin due to sustained release of BMP-2. Figures are adapted with permission from the following: (A) (Sleep et al., 2017) (B) American Society For Clinical Investigation Ref: (Lee et al., 2015). (C) Elsevier Ref: (Holloway et al., 2014). (D) Wiley Ref: (Ma et al., 2015).