Infrapatellar fat pad-derived mesenchymal stem cell-based spheroids enhance their therapeutic efficacy to reverse synovitis and fat pad fibrosis

Stem Cell Research & Therapy

Thomas M. Best¹  Lee D. Kaplan¹  Diego Correa²  Dimitrios Kouroupis²  Melissa A. Willman³ 

[1] Department of Orthopedics, UHealth Sports Medicine Institute, University of Miami, Miller School of Medicine, 1450 NW 10th Ave (3014), 33136, Miami, FL, USA;Department of Orthopedics, UHealth Sports Medicine Institute, University of Miami, Miller School of Medicine, 1450 NW 10th Ave (3014), 33136, Miami, FL, USA;Diabetes Research Institute & Cell Transplantation Center, University of Miami, Miller School of Medicine, 1450 NW 10th Ave (3014), 33136, Miami, FL, USA;Diabetes Research Institute & Cell Transplantation Center, University of Miami, Miller School of Medicine, 1450 NW 10th Ave (3014), 33136, Miami, FL, USA;

关键词: Mesenchymal stem cells (MSC);    Infrapatellar fat pad (IFP);    CD146 subpopulations;    Cell priming;    Spheroid cultures;    Synovitis;    IFP fibrosis;    Osteoarthritis;   

DOI  :  10.1186/s13287-020-02107-6

来源: Springer

【 摘 要 】

BackgroundTo investigate the in vitro and in vivo anti-inflammatory/anti-fibrotic capacity of IFP-MSC manufactured as 3D spheroids. Our hypothesis is that IFP-MSC do not require prior cell priming to acquire a robust immunomodulatory phenotype in vitro in order to efficiently reverse synovitis and IFP fibrosis, and secondarily delay articular cartilage damage in vivo.MethodsHuman IFP-MSC immunophenotype, tripotentiality, and transcriptional profiles were assessed in 3D settings. Multiplex secretomes were assessed in IFP-MSC spheroids [Crude (non-immunoselected), CD146+ or CD146− immunoselected cells] and compared with 2D cultures with and without prior inflammatory/fibrotic cell priming. Functionally, IFP-MSC spheroids were assessed for their immunopotency on human PBMC proliferation and their effect on stimulated synoviocytes with inflammation and fibrotic cues. The anti-inflammatory and anti-fibrotic spheroid properties were further evaluated in vivo in a rat model of acute synovitis/fat pad fibrosis.ResultsSpheroids enhanced IFP-MSC phenotypic, transcriptional, and secretory immunomodulatory profiles compared to 2D cultures. Further, CD146+ IFP-MSC spheroids showed enhanced secretory and transcriptional profiles; however, these attributes were not reflected in a superior capacity to suppress activated PBMC. This suggests that 3D culturing settings are sufficient to induce an enhanced immunomodulatory phenotype in both Crude and CD146-immunoselected IFP-MSC. Crude IFP-MSC spheroids modulated the molecular response of synoviocytes previously exposed to inflammatory cues. Therapeutically, IFP-MSC spheroids retained substance P degradation potential in vivo, while effectively inducing resolution of inflammation/fibrosis of the synovium and fat pad. Furthermore, their presence resulted in arrest of articular cartilage degradation in a rat model of progressive synovitis and fat pad fibrosis.Conclusions3D spheroids confer IFP-MSC a reproducible and enhanced immunomodulatory effect in vitro and in vivo, circumventing the requirement of non-compliant cell priming or selection before administration and thereby streamlining cell products manufacturing protocols.

【 授权许可】

CC BY