机构:[1]Department of Foot and Ankle Surgery, Beijing Tongren Hospital, Capital Medical University, Beijing, 100730, P. R. China.首都医科大学附属北京同仁医院临床科室足踝外科中心[2]State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Chaoyang District, Beijing, 100101, P.R. China.[3]Beijing Institute for Stem Cell and Regenerative Medicine, Chaoyang District, Beijing, 100101, P.R. China.[4]University of Chinese Academy of Sciences, Huairou District, Beijing, 101499, P. R. China.[5]Beijing Institute of Fashion Technology, Beijing, 100029, P.R. China.[6]Department of Orthopaedics, Shanghai Key Laboratory for Prevention and Treatment of Bone and Joint Diseases, Shanghai Institute of Traumatology and Orthopaedics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, P. R. China.
Cartilage equivalents from hydrogels containing chondrocytes exhibit excellent potential in hyaline cartilage regeneration, yet current approaches have limited success at reconstituting the architecture to culture nondifferentiated chondrocytes in vitro. In this study, we report specially designed lacunar hyaluronic acid microcarriers (LHAMC) with mechanotransductive conditions that rapidly form stable hyaluronic acid (HA) N-hydroxy succinimide ester (NHS-ester). Specifically, carboxyl-functionalized HA is linked to collagen type I via amide-crosslinking, and gas foaming produced by ammonium bicarbonate form concave surface of the microcarriers. The temporal three-dimensional culture of chondrocytes on LHAMC uniquely remodels the extracellular matrix to induce hyaline cartilaginous microtissue regeneration and prevents an anaerobic-to-aerobic metabolism transition in response to the geometric constraints. Furthermore, by inhibiting the canonical Wnt pathway, LHAMC prevent β-catenin translocation to the nucleus, repressing chondrocyte dedifferentiation. Additionally, the subcutaneous implantation model indicates that LHAMC display favorable cytocompatibility and drive robust hyaline chondrocyte-derived neocartilage formation. Our findings reveal a novel strategy for regulating chondrocyte dedifferentiation. The current study paves the way for a better understanding of geometrical insight clues into mechanotransduction interaction in regulating cell fate, opening new avenues for advancing tissue engineering. This article is protected by copyright. All rights reserved.This article is protected by copyright. All rights reserved.
基金:
The authors greatly acknowledge the financial support from the National Natural Science Foundation of China (No. 82272473), the Strategic Priority Research Program of the Chinese Academy of Sciences (XDA16020802), CAS Engineering Laboratory for Intelligent Organ Manufacturing (KFJ-PTXM-039), CAS Project for Young Scientists in Basic Research (YSBR-012), Research Equipment Development Program of the Chinese Academy of Sciences (YJKYYQ20190045), K. C. Wong Education Foundation (GJTD-2019-06), Beijing Institute for Stem Cell and Regenerative Medicine Project Incubation Found (Grant No.2022FH110) and Foundation of State Key Laboratory of Robotics (2019-KF-21-12). This work was also supported by the National Natural Science Foundation of China (Grant No. 81773091), the Natural Science Foundation of Beijing Municipality (Grant No. 7212020), the Science and Technology Planning Project of Beijing Municipal Education Commission (KM202110025013), the Beijing Municipal Excellent Talents Project (2020A43).
第一作者机构:[1]Department of Foot and Ankle Surgery, Beijing Tongren Hospital, Capital Medical University, Beijing, 100730, P. R. China.
共同第一作者:
通讯作者:
通讯机构:[2]State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Chaoyang District, Beijing, 100101, P.R. China.[3]Beijing Institute for Stem Cell and Regenerative Medicine, Chaoyang District, Beijing, 100101, P.R. China.[4]University of Chinese Academy of Sciences, Huairou District, Beijing, 101499, P. R. China.