Cartilage regeneration
Organ and tissue development from progenitor cells requires complex interactions and inputs from surrounding cells. Avascular tissues such as cartilage are relatively simple, and the ability to generate cartilage from progenitor cells is promising for treatment of chondrogenic defects such as craniofacial abnormalities. Takanori Takebe and colleagues at Yokohama City University Graduate School of Medicine evaluated the fate of cartilage progenitor cells (CPCs) following transplantation under a transparent cranial window in mice, which allowed long-term observation. Immature murine cartilage underwent a transient vascularization during the maturation process, and transplanted conventionally differentiated human-derived CPCs also temporality vascularized during differentiation. Takebe and colleagues observed an endothelial network inside and adjacent to the immature cartilage transplants, and co-culture of adult-derived human CPCs with HUVECs resulted in extensive CPC proliferation, self- condensation, and organization. Following transplantation, these culture-grown 3D condensed progenitors transiently vascularized and reconstructed elastic cartilage much more effectively than conventionally generated CPCs. Moreover, self-condensed progenitors were amenable to cryopreservation. The results of this study reveal that transient vascularization is an important step in cartilage formation and provide a potential approach for regeneration of patient cartilage from adult-derived CPCs. The accompanying image shows a human-derived 3D condensed progenitor at multiple time points following transplantation under a transparent cranial window. By day 4 the transplant is highly vascularized, and by day 18 these vessels have completely regressed.
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Abstract
Millions of patients worldwide are affected by craniofacial deformations caused by congenital defects or trauma. Current surgical interventions have limited therapeutic outcomes; therefore, methods that would allow cartilage restoration are of great interest. A number of studies on embryonic limb development have shown that chondrogenesis is initiated by cellular condensation, during which mesenchymal progenitors aggregate and form 3D structures. Here, we demonstrated efficient regeneration of avascular elastic cartilage from in vitro–grown mesenchymal condensation, which recapitulated the early stages of chondrogenesis, including transient vascularization. After transplantation of vascularized condensed progenitors into immunodeficient mice, we used an intravital imaging approach to follow cartilage maturation. We determined that endothelial cells are present inside rudimentary cartilage (mesenchymal condensation) prior to cartilage maturation. Recreation of endothelial interactions in culture enabled a recently identified population of adult elastic cartilage progenitors to generate mesenchymal condensation in a self-driven manner, without requiring the support of exogenous inductive factors or scaffold materials. Moreover, the culture-grown 3D condensed adult–derived progenitors were amenable to storage via simple freezing methods and efficiently reconstructed 3D elastic cartilage upon transplantation. Together, our results indicate that transplantation of endothelialized and condensed progenitors represents a promising approach to realizing a regenerative medicine treatment for craniofacial deformations.
Authors
Takanori Takebe, Shinji Kobayashi, Hiromu Suzuki, Mitsuru Mizuno, Yu-Min Chang, Emi Yoshizawa, Masaki Kimura, Ayaka Hori, Jun Asano, Jiro Maegawa, Hideki Taniguchi
Copyright © 2020 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)