Abstract
Bone marrow stromal cells (BMSC) show promise in cartilage repair, and sheep are the most common large animal pre-clinical model.ObjectiveThe objective of this study was to characterise ovine BMSC (oBMSC) in vitro, and to evaluate the capacity of chondrogenic micro-pellets manufactured from oBMSC or ovine articular chondrocytes (oACh) to repair osteochondral defects in sheep.DesignoBMSC were characterised for surface marker expression using flow cytometry and evaluated for tri-lineage differentiation capacity. oBMSC micro-pellets were manufactured in a microwell platform, and chondrogenesis was compared at 2%, 5%, and 20% O2. The capacity of cartilage micro-pellets manufactured from oBMSC or oACh to repair osteochondral defects in adult sheep was evaluated in an 8-week pilot study.ResultsExpanded oBMSC were positive for CD44 and CD146 and negative for CD45. The common adipogenic induction ingredient, 3-Isobutyl-1-methylxanthine (IBMX), was toxic to oBMSC, but adipogenesis could be restored by excluding IBMX from the medium. BMSC chondrogenesis was optimal in a 2% O2 atmosphere. Micro-pellets formed from oBMSC or oACh appeared morphologically similar, but hypertrophic genes were elevated in oBMSC micro-pellets. While oACh micro-pellets formed cartilage-like repair tissue in sheep, oBMSC micro-pellets did not.ConclusionThe sensitivity of oBMSC, compared to human BMSC, to IBMX in standard adipogenic assays highlights species-associated differences. Micro-pellets manufactured from oACh were more effective than micro-pellets manufactured from oBMSC in the repair of osteochondral defects in sheep. While oBMSC can be driven to form cartilage-like tissue in vitro, the effective use of these cells in cartilage repair will depend on the successful mitigation of hypertrophy and tissue integration.
Highlights
Despite considerable investment into bone marrowderived stromal cells (BMSC, sometimes referred to as “mesenchymal stem cells”) as a cell source for cartilage defect repair, far, no Bone marrow stromal cells (BMSC)-based therapies have successfully passed the regulatory and efficacy hurdles required for clinical approval [1]
While ovine articular chondrocytes (oACh) micro-pellets formed cartilage-like repair tissue in sheep, ovine BMSC (oBMSC) micro-pellets did not
Micro-pellets manufactured from oACh were more effective than micro-pellets manufactured from oBMSC in the repair of osteochondral defects in sheep
Summary
Despite considerable investment into bone marrowderived stromal cells (BMSC, sometimes referred to as “mesenchymal stem cells”) as a cell source for cartilage defect repair, far, no BMSC-based therapies have successfully passed the regulatory and efficacy hurdles required for clinical approval [1]. In some studies that use immunocompromised small animals, human tissue is implanted at ectopic sites, typically in subcutaneous pouches on the backs of mice [2, 3]. While this allows for the transplantation of human cells, the implant sites are dissimilar to human joints, as they do not provide mechanical load, and this site is more vascular than joint capsules. Large animal models such as sheep, pigs, goats, or horses are more appropriate for orthopaedic studies due to their joint anatomy, and healing properties being more similar to that of humans [6]. While sheep are the most commonly used large animal for the study of cartilage repair [6], the biology of sheep or ovine BMSC (oBMSC) remains poorly characterised relative to human BMSC (hBMSC)
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