The Wnt5a Receptor, Receptor Tyrosine Kinase-Like Orphan Receptor 2, Is a Predictive Cell Surface Marker of Human Mesenchymal Stem Cells with an Enhanced Capacity for Chondrogenic Differentiation

Abstract

Multipotent mesenchymal stem cells (MSCs) have enormous potential in tissue engineering and regenerative medicine. However, until now, their development for clinical use has been severely limited as they are a mixed population of cells with varying capacities for lineage differentiation and tissue formation. Here, we identify receptor tyrosine kinase‐like orphan receptor 2 (ROR2) as a cell surface marker expressed by those MSCs with an enhanced capacity for cartilage formation. We generated clonal human MSC populations with varying capacities for chondrogenesis. ROR2 was identified through screening for upregulated genes in the most chondrogenic clones. When isolated from uncloned populations, ROR2+ve MSCs were significantly more chondrogenic than either ROR2–ve or unfractionated MSCs. In a sheep cartilage‐repair model, they produced significantly more defect filling with no loss of cartilage quality compared with controls. ROR2+ve MSCs/perivascular cells were present in developing human cartilage, adult bone marrow, and adipose tissue. Their frequency in bone marrow was significantly lower in patients with osteoarthritis (OA) than in controls. However, after isolation of these cells and their initial expansion in vitro, there was greater ROR2 expression in the population derived from OA patients compared with controls. Furthermore, osteoarthritis‐derived MSCs were better able to form cartilage than MSCs from control patients in a tissue engineering assay. We conclude that MSCs expressing high levels of ROR2 provide a defined population capable of predictably enhanced cartilage production. Stem Cells 2017;35:2280–2291

PDGFRα marks distinct perivascular populations with different osteogenic potential within adipose tissue

“…For example, pericytes expressing the Wnt receptor ROR2 demonstrate enhanced potential to undergo cartilage formation. 31 In another example, human pericytes can be distinguished based on aldehyde dehydrogenase expression into more "primitive" and more "differentiated" cell types. 15 Here, PDGFRα marks distinct perivascular osteoprogenitor cell subpopulations within AT.…”

Pericytes for Therapeutic Bone Repair

“…Regarding bone formation, we have recently identified novel surface markers which typify PSC subsets endowed with higher osteogenic potential (Ding, Meyers et al, unpublished results), as was already recently done for pro-fibrotic ability [10] and chondrogenic capacity [56]. Ongoing studies will converge to explain the bone healing effect of pericytes and other regenerative perivascular cells, both natively in situ and following purification and transplantation, and contribute to the development of a refined therapeutic product (Table 3.1).…”

Five Decades Later, Are Mesenchymal Stem Cells Still Relevant?

“…It was recently confirmed that ALDH hi perivascular progenitors are developmentally more primitive than their ALDH lo counterparts (Hardy et al, 2017;Gomez-Salazar et al, in preparation). Perivascular cells and derived MSCs with superior chondrogenic potential have been identified by marker expression (Dickinson et al, 2017) and proximity to the joint (Hindle et al, 2016), while the subset of perivascular adventitial cells that express CD10 is considerably enriched in osteogenic progenitors, at the expense of adipogenic cells (Ding et al, 2019).…”