From Skeletal Development to Tissue Engineering: Lessons from the Micromass Assay

Damage and degeneration of the skeletal elements due to disease, trauma, and aging lead to a significant health and economical burden. To reduce this burden, skeletal tissue engineering strategies aim to regenerate functional bone and cartilage in the adult body. However, challenges still exist. Such challenges involve the identification of the external cues that determine differentiation, how to control chondrocyte hypertrophy, and how to achieve specific tissue patterns and boundaries. To address these issues, it could be insightful to look at skeletal development, a robust morphogenetic process that takes place during embryonic development and is commonly modeled in vitro by the micromass assay. In this review, we investigate what the tissue engineering field can learn from this assay. By comparing embryonic skeletal precursor cells from different anatomic locations and developmental stages in micromass, the external cues that guide lineage commitment can be identified. The signaling pathways regulating chondrocyte hypertrophy, and the cues required for tissue patterning, can be elucidated by combining the micromass assay with genetic, molecular, and engineering tools. The lessons from the micromass assay are limited by two major differences between developmental and regenerative skeletogenesis: cell type and scale. We highlight an important difference between embryonic and adult skeletal progenitor cells, in that adult progenitors are not able to form mesenchymal condensations spontaneously. Also, the mechanisms of tissue patterning need to be adjusted to the larger tissue engineering constructs. In conclusion, mechanistic insights of skeletal tissue generation gained from the micromass model could lead to improved tissue engineering strategies and constructs.