Concise review: unraveling stem cell cocultures in regenerative medicine: which cell interactions steer cartilage regeneration and how?

Abstract

Cartilage damage and osteoarthritis (OA) impose an important burden on society, leaving both young, active patients and older patients disabled and affecting quality of life. In particular, cartilage injury not only imparts acute loss of function but also predisposes to OA. The increase in knowledge of the consequences of these diseases and the exponential growth in research of regenerative medicine have given rise to different treatment types. Of these, cell-based treatments are increasingly applied because they have the potential to regenerate cartilage, treat symptoms, and ultimately prevent or delay OA. Although these approaches give promising results, they require a costly in vitro cell culture procedure. The answer may lie in single-stage procedures that, by using cell combinations, render in vitro expansion redundant. In the last two decades, cocultures of cartilage cells and a variety of (mesenchymal) stem cells have shown promising results as different studies report cartilage regeneration in vitro and in vivo. However, there is considerable debate regarding the mechanisms and cellular interactions that lead to chondrogenesis in these models. This review, which included 52 papers, provides a systematic overview of the data presented in the literature and tries to elucidate the mechanisms that lead to chondrogenesis in stem cell cocultures with cartilage cells. It could serve as a basis for research groups and clinicians aiming at designing and implementing combined cellular technologies for single-stage cartilage repair and treatment or prevention of OA.

Keywords: Bone marrow stromal cells; Cellular therapy; Chondrogenesis; Clinical translation; Marrow stromal stem cells; Mesenchymal stem cells; Skeleton.

Figure 1.

The three theories of the coculture approach. (A): After mixing chondrocytes and MSCs, chondrocytes stimulate MSCs to differentiate to the chondrogenic lineage. (B): Coculture of chondrocytes and MSCs results in chondroinduction; that is, MSCs excrete trophic factors such as FGF-1 and TGF-β that stimulate chondrocyte proliferation. (C): MSC differentiation plus chondroinduction: both chondroinduction and MSC differentiation contribute to chondrogenesis. Abbreviations: FGF-1, fibroblast growth factor 1; MSC, mesenchymal stem cell; TGF-β, transforming growth factor β.

Figure 2.

Literature search flowchart. Abbreviation: IVD, intervertebral disc.