Cellular Plasticity in Musculoskeletal Development, Regeneration, and Disease

Abstract

In this review, we highlight themes from a recent workshop focused on "Plasticity of Cell Fate in Musculoskeletal Tissues" held at the Orthopaedic Research Society's 2019 annual meeting. Experts in the field provided examples of mesenchymal cell plasticity during normal musculoskeletal development, regeneration, and disease. A thorough understanding of the biology underpinning mesenchymal cell plasticity may offer a roadmap for promoting regeneration while attenuating pathologic differentiation. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 38:708-718, 2020.

Keywords: heterotopic ossification; mesenchymal plasticity; musculoskeletal development; regeneration; transdifferentiation.

Figure 1.. Epigenetic ‘subway map’ of in vitro differentiation from pluripotency, reprogramming, and transdifferentiation.

The arrows and their directionality between differentiated cell types are based on the literature showing successful fate transitions in-vitro. For example, fibroblasts can be induced toward chondrogenesis but have not been differentiated toward erythrocytes. In most cases, cells do not undergo direct transdifferentiation, but pass through a de-differentiated state prior to re-differentiation.

Figure 2.. Schematic diagram showing the plasticity of hypertrophic chondrocytes in development and in chondrodysplasia.

During normal endochondral bone formation, chondrocytes undergo a cascade of proliferation, maturation and hypertrophy. HCs then are transformed by an unknown mechanism to become osteoblasts and osteocytes. In a MCDS mouse model, HCs revert to a pHC-like state, thereby alleviating ER stress. The ISR, through its preferential translation of ATF4 directly causes ectopic activation of Sox9, which mediates reprogramming of HCs. The cells survive but endochondral ossification is delayed. PC: proliferating chondrocyte; pHC: prehypertrophic chondrocyte; HC: hypertrophic chondrocyte. Genes specifically expressed in each cell type are listed.

Figure 3.. Overview of major tissue types during mouse digit tip regeneration.

Both images are schematized cross sections through mouse digit tips; only major tissue types are depicted: orange = epidermis (with dorsal hair follicles and ventral sweat glands); pink = nail plate; white = connective tissues; purple = tendon; blue = bone; red = blood vessels (capillaries not shown); green = nerves (distal axon branching not shown). (TOP) Unamputated digit where dotted arrow shows level of amputation permissive for regeneration. (BOTTOM) Blastema stage regenerating digit tip where progenitor cells in the blastema remain lineage restricted to their original tissue type.