Mesenchymal Stem Cell Stimulation of Tissue Growth Depends on Differentiation State

Abstract

The osteochondral microenvironment involves a complex milieu of cues that facilitate proper tissue development, homeostasis, and repair. This environment is disrupted in disease states such as osteoarthritis. Mesenchymal stem cells (MSCs) are under clinical investigation for the treatment of osteoarthritis given their capacity to differentiate into chondrocytes as well as to secrete a wide array of biologically active factors that support cell proliferation and tissue formation. In fact, the therapeutic action of these cells in many clinical applications is now thought to be at least partially dependent on their secretory capacity. Previous work demonstrated that MSCs were capable of stimulating chondrocyte growth and tissue production, whereas tissue-derived osteoblasts were not stimulatory. This study investigated the stimulatory capacity of MSCs during osteogenesis and the impact of MSC phenotype on cartilage stimulation. Cell interactions were examined in 3 coculture systems to confirm that trends were not dependent on material: traditional cell culture insert coculture, bilayered poly(ethylene glycol) gels, and a scaffold comprised of a layer of poly(ethylene glycol) polymerized onto a poly(lactic-co-glycolic) acid-based scaffold. Results demonstrated that MSCs predifferentiated toward an osteogenic phenotype for 3 days exhibited enhanced stimulation of chondrocyte extracellular matrix production, whereas longer periods of predifferentiation decreased the magnitude of observed stimulation. Further, tissue formation by the MSCs themselves showed greater dependence on the coculture system than the presence of other cells or length of predifferentiation.

Osteochondral defect repair using bilayered hydrogels encapsulating both chondrogenically and osteogenically pre-differentiated mesenchymal stem cells in a rabbit model

“…From previous findings, we confirmed that OS cells, when cultured with undifferentiated MSCs in a bilayered hydrogel construct, stimulated the chondrogenic differentiation of the latter likely via paracrine effects 24, 30, 34–36 . In a parallel study, CG cells, when co-cultured with OS cells, displayed enhanced chondrogenic gene expression for type II collagen and aggrecan as well as increased GAG production in vitro 24 .…”

Lysophosphatidic Acid Protects Human Mesenchymal Stromal Cells from Differentiation-Dependent Vulnerability to Apoptosis

“…Undifferentiated MSC can be used to support angiogenesis in defect sites or modulate immune responses, 21 while treatment strategies that target direct bone repair may benefit from inducing MSC toward the osteoblastic lineage before implantation to promote rapid bone formation and calcium deposition. 22,23 Since MSC exhibit unique secretory and stimulatory characteristics depending on their differentiation state, 4,24 it is important to account for variations in cellular responses to LPA at different degrees of differentiation.…”

Sources of Adult Mesenchymal Stem Cells and their Applicability for Musculoskeletal Applications

“…A recent study by Rothenberg et al takes the view that it may not necessarily be the environment we expose the MSC to which determines the type of lineage they differentiate into. It could also be the bioactive factors which the MSC themselves secrete which determine the type of tissue produced [22]. In other words, the MSC may not just act as sources of cells for us to manipulate, but they may themselves be reactant to their microenvironmental conditions, before exposing them to artificial conditions, to allow them to secrete certain factors such as Matrix Metalloproteinase (MMPs) and Transforming Growth Factor 1 (TGF 1) to determine the type of tissue produced.…”

“…Taking this idea forward, it would therefore be important to consider how we can manipulate the MSC in the predifferentiation state before the MSC has decided which factors it is going to secrete [22] and hence, which subsequent tissue it will produce. This study also proposes that using scaffolds such as gels mixed with MSC can stimulate the MSC in their pre-differentiation state to be more likely to secrete certain factors.…”

“…The study by Scotti et al highlights the fact that most MSC generate bone by a process similar to intramembranous ossification [22]. In order to push the MSC down an osteogenic pathway via endochondral ossification, a mature MSC hypertrophic chondrocyte template needs to be achieved initially whereby the cells express high levels of Type X collagen.…”