Transplantation of human ESC-derived mesenchymal stem cell spheroids ameliorates spontaneous osteoarthritis in rhesus macaques

Abstract

It has been demonstrated that mesenchymal stem cells (MSCs) differentiated from human embryonic stem cells (hESCs), name EMSCs, can treat a variety of autoimmune and inflammatory diseases, with similar efficacies to those achieved with MSCs derived from somatic tissues such as bone marrow (BMSCs). The chance increases even higher for EMSCs, than somatic tissue derived MSCs​, to become a cell drug as the former can be produced in large scale from an unlimited hESC line with easier quality control and less biosafety concern. We have further demonstrated that both human ESCs and EMSCs, after aggregation to form spheroids, can tolerate hypoxic and ambient conditions (AC) for over 4 and 10 days, respectively, without loss of their viability and alteration of their functions. Based on these advantages, we decided to test whether EMSC spheroids, made in large quantity and delivered through a long-term distance at AC, can treat osteoarthritis spontaneously developed in rhesus macaques (M. mulatta) monkeys as well as the allogenic MSCs.Methods: Xenogeneic AC-transported EMSC spheroids or allogenic BMSCs were injected into the articular cavity of both knees of the monkeys at 3 animals per group. Another two macaques were injected the same way with saline as controls.Results: Both EMSCs and BMSCs groups showed significant amelioration indicated by the reduction of swelling joint size and amplification of keen flare angle post-treatment, compared to the control group. Examinations via X-ray and MRI also indicated the decrease of inflammation and osteophyma, and recovery of the synovium and cartilage in both treated groups. No sign of allergy or graft versus host disease was observed in the animals.Conclusion: Our results demonstrate that human EMSC spheroids can prevent the osteoarthtitis progression and ameliorate osteoarthritis in the rhesus macaques as well as allogenic BMSCs, and this study shall help advance the clinical application of EMSCs.

Research Progress on Stem Cell Therapies for Articular Cartilage Regeneration

“…The pathological process of OA in these quadrupeds may be quite different from that in humans. One study used a model of OA in primates (rhesus monkeys) [ 60 ]. Encouragingly, the results of this study showed that both xenogenic ESC-derived MSCs (EMSCs) and allogeneic BMSC transplantation had therapeutic effects on knee joint OA in rhesus monkeys, and the results were better than those in the control group.…”

Inflammation-Modulating Hydrogels for Osteoarthritis Cartilage Tissue Engineering

“…Indeed, Hwang et al, demonstrated that ESCs expanded in co-culture with chondrocytes resulted in more homogeneous ESC-derived cartilage tissue both in vitro and in vivo [31]. Some studies have generated MSCs derived from ESCs and utilized their exosomes [32] and spheroids [33] in murine and primate OA models. Similarly, exosomes secreted by iPSC-derived MSCs were used in regenerating OA in a rat model [34].…”

Effects of cryopreservation and long-term culture on biological characteristics and proteomic profiles of human umbilical cord-derived mesenchymal stem cells

“…For chondrogenic differentiation, 2 × 10 5 hUC-MSCs were pelleted in 15-mL centrifuge tubes and cultured with the chondrogenic differentiation medium (Biological Industries, Israel) for 21 days and the medium was refreshed every 3 days. The chondroid pellets were sectioned by a freezing microtome and the slices were stained with toluidine blue in a MSCs Chondro-Staining Kit (XP Biomed Ltd., Shanghai, China) according the instructions [15].…”