PMID- 33812074
OWN - NLM
STAT- MEDLINE
DCOM- 20210531
LR  - 20210531
IS  - 1878-7568 (Electronic)
IS  - 1742-7061 (Linking)
VI  - 127
DP  - 2021 Jun
TI  - Cell-free decellularized cartilage extracellular matrix scaffolds combined with 
      interleukin 4 promote osteochondral repair through immunomodulatory macrophages: 
      In vitro and in vivo preclinical study.
PG  - 131-145
LID - S1742-7061(21)00204-X [pii]
LID - 10.1016/j.actbio.2021.03.054 [doi]
AB  - Cartilage regeneration is a complex physiological process. Synovial macrophages 
      play a critical immunomodulatory role in the acute inflammatory response 
      surrounding joint injury. Due to the contrasting differences and heterogeneity of 
      macrophage, the phenotype of macrophages are the key determinants of the healing 
      response after cartilage injury. Biomaterials derived from extracellular matrix 
      have been used for the repair and reconstruction of a variety of tissues by 
      modulating the host macrophage response. However, the immunomodulatory effect of 
      decellularized cartilage extracellular matrix (ECM) on macrophages has not been 
      elucidated. It is necessary to clarify the immunomodulatory properties of 
      decellularized cartilage matrix (DCM) to guide the design of cartilage 
      regeneration materials. Here, we prepared porcine articular cartilage derived DCM 
      and determined the response of mouse bone marrow-derived macrophages (BMDMs) to 
      the pepsin-solubilized DCM (PDCM) in vitro. Macrophages activated by the PDCM 
      could promote bone marrow-derived mesenchymal stem cells (BMSCs) invasion, 
      migration, proliferation, and chondrogenic differentiation. Then, we verified 
      that early optimization of the immunomodulatory effects of the cell-free DCM 
      scaffold using IL-4 in vivo could achieve good cartilage regeneration in a rat 
      knee osteochondral defect model. Therefore, this decellularized cartilage ECM 
      scaffold combined with accurate and active immunomodulatory strategies provides a 
      new approach for the development of cartilage regeneration materials. STATEMENT 
      OF SIGNIFICANCE: This work reports a decellularized cartilage extracellular 
      matrix (DCM) scaffold combined with an accurate and active immunomodulatory 
      strategy to improve cartilage regeneration. Our findings demonstrated that the 
      pepsin-solubilized DCM (PDCM) activated bone marrow-derived macrophages to 
      polarize to a constructive macrophage phenotype. These polarized macrophages 
      promoted bone marrow-derived mesenchymal stem cell invasion, migration, 
      proliferation, and chondrogenic differentiation. DCM scaffolds combined with 
      early-stage intra-articular injection of IL-4 created a wound-healing 
      microenvironment and improved cartilage regeneration in a rat knee osteochondral 
      defect model.
CI  - Copyright (c) 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.
FAU - Tian, Guangzhao
AU  - Tian G
AD  - Institute of Orthopedics, The First Medical Center, Chinese PLA General Hospital, 
      Beijing Key Lab of Regenerative Medicine in Orthopedics, Key Laboratory of 
      Musculoskeletal Trauma and War Injuries PLA, No. 28 Fuxing Road, Haidian 
      District, Beijing 100853, China; School of Medicine, Nankai University, Tianjin 
      300071, China.
FAU - Jiang, Shuangpeng
AU  - Jiang S
AD  - Institute of Orthopedics, The First Medical Center, Chinese PLA General Hospital, 
      Beijing Key Lab of Regenerative Medicine in Orthopedics, Key Laboratory of 
      Musculoskeletal Trauma and War Injuries PLA, No. 28 Fuxing Road, Haidian 
      District, Beijing 100853, China.
FAU - Li, Junqi
AU  - Li J
AD  - Institute of Orthopedics, The First Medical Center, Chinese PLA General Hospital, 
      Beijing Key Lab of Regenerative Medicine in Orthopedics, Key Laboratory of 
      Musculoskeletal Trauma and War Injuries PLA, No. 28 Fuxing Road, Haidian 
      District, Beijing 100853, China.
FAU - Wei, Fu
AU  - Wei F
AD  - Institute of Orthopedics, The First Medical Center, Chinese PLA General Hospital, 
      Beijing Key Lab of Regenerative Medicine in Orthopedics, Key Laboratory of 
      Musculoskeletal Trauma and War Injuries PLA, No. 28 Fuxing Road, Haidian 
      District, Beijing 100853, China.
FAU - Li, Xu
AU  - Li X
AD  - Institute of Orthopedics, The First Medical Center, Chinese PLA General Hospital, 
      Beijing Key Lab of Regenerative Medicine in Orthopedics, Key Laboratory of 
      Musculoskeletal Trauma and War Injuries PLA, No. 28 Fuxing Road, Haidian 
      District, Beijing 100853, China.
FAU - Ding, Yi
AU  - Ding Y
AD  - State Key Laboratory of Proteomics, National Center for Protein Sciences 
      (Beijing), Beijing Institute of Lifeomics, 100850 Beijing, China.
FAU - Yang, Zhen
AU  - Yang Z
AD  - Institute of Orthopedics, The First Medical Center, Chinese PLA General Hospital, 
      Beijing Key Lab of Regenerative Medicine in Orthopedics, Key Laboratory of 
      Musculoskeletal Trauma and War Injuries PLA, No. 28 Fuxing Road, Haidian 
      District, Beijing 100853, China; School of Medicine, Nankai University, Tianjin 
      300071, China.
FAU - Sun, Zhiqiang
AU  - Sun Z
AD  - Institute of Orthopedics, The First Medical Center, Chinese PLA General Hospital, 
      Beijing Key Lab of Regenerative Medicine in Orthopedics, Key Laboratory of 
      Musculoskeletal Trauma and War Injuries PLA, No. 28 Fuxing Road, Haidian 
      District, Beijing 100853, China; School of Medicine, Nankai University, Tianjin 
      300071, China.
FAU - Zha, Kangkang
AU  - Zha K
AD  - Institute of Orthopedics, The First Medical Center, Chinese PLA General Hospital, 
      Beijing Key Lab of Regenerative Medicine in Orthopedics, Key Laboratory of 
      Musculoskeletal Trauma and War Injuries PLA, No. 28 Fuxing Road, Haidian 
      District, Beijing 100853, China; School of Medicine, Nankai University, Tianjin 
      300071, China.
FAU - Wang, FuXin
AU  - Wang F
AD  - Institute of Orthopedics, The First Medical Center, Chinese PLA General Hospital, 
      Beijing Key Lab of Regenerative Medicine in Orthopedics, Key Laboratory of 
      Musculoskeletal Trauma and War Injuries PLA, No. 28 Fuxing Road, Haidian 
      District, Beijing 100853, China.
FAU - Huang, Bo
AU  - Huang B
AD  - Institute of Orthopedics, The First Medical Center, Chinese PLA General Hospital, 
      Beijing Key Lab of Regenerative Medicine in Orthopedics, Key Laboratory of 
      Musculoskeletal Trauma and War Injuries PLA, No. 28 Fuxing Road, Haidian 
      District, Beijing 100853, China.
FAU - Peng, Liqing
AU  - Peng L
AD  - Institute of Orthopedics, The First Medical Center, Chinese PLA General Hospital, 
      Beijing Key Lab of Regenerative Medicine in Orthopedics, Key Laboratory of 
      Musculoskeletal Trauma and War Injuries PLA, No. 28 Fuxing Road, Haidian 
      District, Beijing 100853, China.
FAU - Wang, Qiuming
AU  - Wang Q
AD  - Institute of Orthopedics, The First Medical Center, Chinese PLA General Hospital, 
      Beijing Key Lab of Regenerative Medicine in Orthopedics, Key Laboratory of 
      Musculoskeletal Trauma and War Injuries PLA, No. 28 Fuxing Road, Haidian 
      District, Beijing 100853, China.
FAU - Tian, Zhuang
AU  - Tian Z
AD  - Institute of Orthopedics, The First Medical Center, Chinese PLA General Hospital, 
      Beijing Key Lab of Regenerative Medicine in Orthopedics, Key Laboratory of 
      Musculoskeletal Trauma and War Injuries PLA, No. 28 Fuxing Road, Haidian 
      District, Beijing 100853, China.
FAU - Yang, Xi
AU  - Yang X
AD  - State Key Laboratory of Proteomics, National Center for Protein Sciences 
      (Beijing), Beijing Institute of Lifeomics, 100850 Beijing, China; General 
      Hospital of Xinjiang Military Command, 830000 Urumqi, China.
FAU - Wang, Zhigang
AU  - Wang Z
AD  - Institute of Orthopedics, The First Medical Center, Chinese PLA General Hospital, 
      Beijing 100853, China.
FAU - Guo, Quanyi
AU  - Guo Q
AD  - Institute of Orthopedics, The First Medical Center, Chinese PLA General Hospital, 
      Beijing Key Lab of Regenerative Medicine in Orthopedics, Key Laboratory of 
      Musculoskeletal Trauma and War Injuries PLA, No. 28 Fuxing Road, Haidian 
      District, Beijing 100853, China. Electronic address: doctorguo_301@163.com.
FAU - Guo, Weimin
AU  - Guo W
AD  - Institute of Orthopedics, The First Medical Center, Chinese PLA General Hospital, 
      Beijing Key Lab of Regenerative Medicine in Orthopedics, Key Laboratory of 
      Musculoskeletal Trauma and War Injuries PLA, No. 28 Fuxing Road, Haidian 
      District, Beijing 100853, China; Department of Orthopedic Surgery, First 
      Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China. 
      Electronic address: guowm5@mail.sysu.edu.cn.
FAU - Liu, Shuyun
AU  - Liu S
AD  - Institute of Orthopedics, The First Medical Center, Chinese PLA General Hospital, 
      Beijing Key Lab of Regenerative Medicine in Orthopedics, Key Laboratory of 
      Musculoskeletal Trauma and War Injuries PLA, No. 28 Fuxing Road, Haidian 
      District, Beijing 100853, China. Electronic address: clear_ann@163.com.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20210331
PL  - England
TA  - Acta Biomater
JT  - Acta biomaterialia
JID - 101233144
RN  - 207137-56-2 (Interleukin-4)
SB  - IM
MH  - Animals
MH  - *Cartilage, Articular
MH  - Chondrogenesis
MH  - Extracellular Matrix
MH  - *Interleukin-4
MH  - Macrophages
MH  - Mice
MH  - Rats
MH  - Swine
MH  - Tissue Engineering
MH  - Tissue Scaffolds
OTO - NOTNLM
OT  - Cartilage tissue engineering
OT  - Decellularized extracellular matrix
OT  - Immunomodulation
OT  - Macrophage polarization
OT  - Stem cell recruitment
COIS- Declaration of Competing Interest The authors declare that they have no known 
      competing financial interests or personal relationships that could have appeared 
      to influence the work reported in this paper.
EDAT- 2021/04/04 06:00
MHDA- 2021/06/01 06:00
CRDT- 2021/04/03 20:12
PHST- 2021/01/27 00:00 [received]
PHST- 2021/03/05 00:00 [revised]
PHST- 2021/03/23 00:00 [accepted]
PHST- 2021/04/04 06:00 [pubmed]
PHST- 2021/06/01 06:00 [medline]
PHST- 2021/04/03 20:12 [entrez]
AID - S1742-7061(21)00204-X [pii]
AID - 10.1016/j.actbio.2021.03.054 [doi]
PST - ppublish
SO  - Acta Biomater. 2021 Jun;127:131-145. doi: 10.1016/j.actbio.2021.03.054. Epub 2021 
      Mar 31.