TY - JOUR
T1 - Regeneration of hyaline-like cartilage in situ with SOX9 stimulation of bone marrow-derived mesenchymal stem cells
AU - Zhang, Xiaowei
AU - Wu, Shili
AU - Naccarato, Ty
AU - Prakash-Damani, Manan
AU - Chou, Yuan
AU - Chu, Cong Qiu
AU - Zhu, Yong
N1 - Funding Information:
XZ and YC have nothing to disclose. CQC received research grants from VivoScript, Inc and US Department of Veterans Affairs (IBX002858). SW, TN, MPD and YZ are employees of VivoScript, Inc, an early stage biotechnology company developing protein drugs for cartilage repair. SW, YZ and CQC have jointly filed the following patent applications: “Compositions and Methods for Reprogramming Cells without Genetic Modification for Repairing Cartilage Damage” (PCT/US2012/047495). “Methods for Repairing Cartilage Damage” (PCT/US2015/034309). This does not alter our adherence to PLOS ONE policies on sharing data and materials.
Funding Information:
This was supported by a grant from VivoScript, Inc (to CQC) and VA Merit Review (IBX002858, to CQC). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The funder provided support in the form of salaries for authors SW, TN, MPD and YZ, but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the “Author Contributions” section. The authors would like to thank Dr. Brian Johnstone for providing human bone marrow mesenchymal stem cells and Ms. Lijuan Liu for technical assistance in histology.
Publisher Copyright:
© This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.
PY - 2017/6
Y1 - 2017/6
N2 - Microfracture, a common procedure for treatment of cartilage injury, induces fibrocartilage repair by recruiting bone marrow derived mesenchymal stem cells (MSC) to the site of cartilage injury. However, fibrocartilage is inferior biomechanically to hyaline cartilage. SRY-type high-mobility group box-9 (SOX9) is a master regulator of chondrogenesis by promoting proliferation and differentiation of MSC into chondrocytes. In this study we aimed to test the therapeutic potential of cell penetrating recombinant SOX9 protein in regeneration of hyaline cartilage in situ at the site of cartilage injury. We generated a recombinant SOX9 protein which was fused with super positively charged green fluorescence protein (GFP) (scSOX9) to facilitate cell penetration. scSOX9 was able to induce chondrogenesis of bone marrow derived MSC in vitro. In a rabbit cartilage injury model, scSOX9 in combination with microfracture significantly improved quality of repaired cartilage as shown by macroscopic appearance. Histological analysis revealed that the reparative tissue induced by microfracture with scSOX9 had features of hyaline cartilage; and collagen type II to type I ratio was similar to that in normal cartilage. This short term in vivo study demonstrated that when administered at the site of microfracture, scSOX9 was able to induce reparative tissue with features of hyaline cartilage.
AB - Microfracture, a common procedure for treatment of cartilage injury, induces fibrocartilage repair by recruiting bone marrow derived mesenchymal stem cells (MSC) to the site of cartilage injury. However, fibrocartilage is inferior biomechanically to hyaline cartilage. SRY-type high-mobility group box-9 (SOX9) is a master regulator of chondrogenesis by promoting proliferation and differentiation of MSC into chondrocytes. In this study we aimed to test the therapeutic potential of cell penetrating recombinant SOX9 protein in regeneration of hyaline cartilage in situ at the site of cartilage injury. We generated a recombinant SOX9 protein which was fused with super positively charged green fluorescence protein (GFP) (scSOX9) to facilitate cell penetration. scSOX9 was able to induce chondrogenesis of bone marrow derived MSC in vitro. In a rabbit cartilage injury model, scSOX9 in combination with microfracture significantly improved quality of repaired cartilage as shown by macroscopic appearance. Histological analysis revealed that the reparative tissue induced by microfracture with scSOX9 had features of hyaline cartilage; and collagen type II to type I ratio was similar to that in normal cartilage. This short term in vivo study demonstrated that when administered at the site of microfracture, scSOX9 was able to induce reparative tissue with features of hyaline cartilage.
UR - http://www.scopus.com/inward/record.url?scp=85021639435&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85021639435&partnerID=8YFLogxK
U2 - 10.1371/journal.pone.0180138
DO - 10.1371/journal.pone.0180138
M3 - Article
C2 - 28666028
AN - SCOPUS:85021639435
VL - 12
JO - PLoS One
JF - PLoS One
SN - 1932-6203
IS - 6
M1 - e0180138
ER -