Attenuation of Knee Osteoarthritis Progression in Mice through Polarization of M2 Macrophages by Intra-Articular Transplantation of Non-Cultured Human Adipose-Derived Regenerative Cells.

Kohei Kamada,Tomoyuki Matsumoto,Takehiko Matsushita,Ryosuke Kuroda,Satoshi Sobajima,Hideki Iwaguro,Takahiro Yamashita

doi:10.3390/jcm10194309

Abstract

Adipose-derived regenerative cells (ADRCs) are non-cultured heterogeneous or mixed populations of cells obtained from adipose tissue by collagenase digestion. The injection of ADRCs have been tried clinically for the treatment of osteoarthritis (OA). The purpose of this study was to evaluate the effect of intra-articular transplantation of human ADRCs on OA progression in mice and the effect of ADRCs on macrophage polarization. In in vivo experiments, BALB/c-nu mice with knee OA received intra-articular transplantation of either phosphate buffered-saline or human ADRCs. OA progression was evaluated histologically and significantly attenuated in the ADRC group at both four and eight weeks postoperatively. The expression of OA-related proteins in the cartilage and macrophage-associated markers in the synovium were examined by immunohistochemistry. The numbers of MMP-13-, ADAMTS-5-, IL-1β-, IL-6- and iNOS-positive cells significantly decreased, and type II collagen- and CD206-positive cells were more frequently detected in the ADRC group compared with that in the control group. In vitro co-culture experiments showed that ADRCs induced macrophage polarization toward M2. The results of this study suggest that the intra-articular transplantation of human ADRCs could attenuate OA progression possibly by reducing catabolic factors in chondrocytes and modulating macrophage polarization.

Highlights

Osteoarthritis (OA) of the knee is a common disease and one of the major causes of joint dysfunction and physical disability in the elderly [1]
OA progression was observed in both groups; the histopathological score, based on the Osteoarthritis Research Society International (OARSI) OA histopathologygrading system, of the medial femoral condyle and tibial condyle in the Adipose-derived regenerative cells (ADRCs)-treated group was significantly lower than that in the control group at both four and eight weeks post-surgery (Figure 2)
Immunohistochemical analysis showed that the number of type II collagen-positive cells was significantly higher, whereas the number of MMP-13, ADAMTS-5, IL-6, and IL1β-positive chondrocytes were significantly lower, in the ADRC-treated group compared with that in the control group at both four and eight weeks post-surgery (Figure 3)

Summary

Introduction

Osteoarthritis (OA) of the knee is a common disease and one of the major causes of joint dysfunction and physical disability in the elderly [1]. Since articular cartilage is an avascular tissue and poor in cellular components, drug accessibility, and its self-healing capacity are relatively low. Due to this unique tissue structure, treatment of OA is challenging, and to date, disease-modifying drugs for OA have not been developed. Adipose tissue is a source of stem cells and contains mesenchymal adiposederived stem cells (ADSCs), which have been shown to undergo adipogenic, osteogenic, chondrogenic, neurogenic, and myogenic differentiation in vitro [2]. Adipose tissue is relatively easy to harvest by liposuction and contains an abundance of stem cells, wherein approximately 5% of adipose tissue-derived nucleated cells have characteristic stem cell phenotypes; in contrast, only 0.0001–0.01% of bone marrow-derived mesenchymal cells show stem cell properties [2,3]. The cost of cell culture, two-step surgery, cell harvest, and implantation impede its widespread use in clinical settings

Objectives

Methods

Results

Discussion

Conclusion