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Transient vascularization of transplanted human adult–derived progenitors promotes self-organizing cartilage
Takanori Takebe, … , Jiro Maegawa, Hideki Taniguchi
Takanori Takebe, … , Jiro Maegawa, Hideki Taniguchi
Published September 9, 2014
Citation Information: J Clin Invest. 2014;124(10):4325-4334. https://doi.org/10.1172/JCI76443.
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Technical Advance Stem cells

Transient vascularization of transplanted human adult–derived progenitors promotes self-organizing cartilage

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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

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Figure 4

Recapitulation of transient vascularization prior to human cartilage progenitor maturation.

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Recapitulation of transient vascularization prior to human cartilage pro...
(A) Macroscopic observation of transplanted day-2 self-condensed hCPCs with HUVECs at multiple time points, showing the initial vascularization and subsequent vessel regression. Scale bar: 2 mm. (B) Intravital visualization of the vasculature inside the transplanted tissues along with the surrounding recipient vessels. Green, dextran; red, CPCs; blue, mouse-specific Alexa Fluor 647–conjugated CD31. Scale bars: 500 μm and 75 μm (inset). (C) Time-dependent changes in the number of transplanted HUVECs over CPCs. Upper panels are representative images for the subsequent quantification analysis. Data represent the mean ± SD (n = 3, *P < 0.01). Green, HUVECs; red, CPCs. (D–G) Safranin O (D) and EVG (E) staining of vascularized tissue transplants at day 30 indicated a significant number of cartilage ECM proteins characteristic of elastic cartilage. Aggrecan (green) and collagen I (red) coimmunostaining (F) showed that the reconstructed cartilage developed both perichondral and chondral layers. Human CD31 immunostaining (G) showed that human endothelial cells remained in the perichondral layer, similar to that observed in normal ear cartilage. Scale bars: 100 μm.

Copyright © 2023 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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