The socioeconomic burden of chronic back pain related to intervertebral disc (IVD) disease is high and current treatments are only symptomatic. Minimally invasive strategies that promote biological IVD repair should address this unmet need. Notochordal cells (NCs) are replaced by chondrocyte-like cells (CLCs) during IVD maturation and degeneration. The regenerative potential of NC-secreted substances on CLCs and mesenchymal stromal cells (MSCs) has already been demonstrated. However, identification of these substances remains elusive. Innovatively, this study exploits the regenerative NC potential by using healthy porcine NC-derived matrix (NCM) and employs the dog as a clinically relevant translational model. NCM increased the glycosaminoglycan and DNA content of human and canine CLC aggregates and facilitated chondrogenic differentiation of canine MSCs in vitro. Based on these results, NCM, MSCs and NCM+MSCs were injected in mildly (spontaneously) and moderately (induced) degenerated canine IVDs in vivo and, after six months of treatment, were analyzed. NCM injected in moderately (induced) degenerated canine IVDs exerted beneficial effects at the macroscopic and MRI level, induced collagen type II-rich extracellular matrix production, improved the disc height, and ameliorated local inflammation. MSCs exerted no (additive) effects. In conclusion, NCM induced in vivo regenerative effects on degenerated canine IVDs. NCM may, comparable to demineralized bone matrix in bone regeneration, serve as ‘instructive matrix’, by locally releasing growth factors and facilitating tissue repair. Therefore, intradiscal NCM injection could be a promising regenerative treatment for IVD disease, circumventing the cumbersome identification of bioactive NC-secreted substances.
Objective Joint distraction triggers intrinsic cartilage repair in animal models of osteoarthritis (OA), corroborating observations in human OA patients treated with joint distraction. The present study explores the still largely elusive mechanism initiating this repair process. Design Unilateral OA was induced in the knee joint of 8 dogs using the groove model; the contralateral joint served as a control. After 10 weeks, 4 animals received joint distraction, the other 4 serving as OA controls. Halfway the distraction period (after 4 weeks of a standard 8-week distraction treatment), all animals were euthanized, and joint tissues were collected. A targeted quantitative reverse transcription polymerase chain reaction (qRT-PCR) analysis was performed of commonly involved processes including matrix catabolism/anabolism, inflammation, and known signaling pathways in OA. In addition, cartilage changes were determined on tissue sections using the canine OARSI (Osteoarthritis Research Society International) histopathology score and collagen type II (COL2A1) immunostaining. Results Midway distraction, the distracted OA joint showed an upregulation of proteolytic genes, for example, ADAMTS5, MMP9, MMP13, compared to OA alone and the healthy joints, which correlated with an increased OARSI score. Additionally, genes of the transforming growth factor (TGF)-β and Notch pathway, and markers associated with progenitor cells were increased. Conclusions Joint distraction initiates both catabolic and anabolic transcriptional responses. The enhanced turnover, and thereby renewal of the matrix, could be the key to the cartilage repair observed in the months after joint distraction.
Liver-derived multipotent stromal cells (L-MSCs) may prove preferable for treatment strategies of liver diseases, in comparison to the widely studied bone marrow-derived MSCs (BM-MSCs). Canines are a large animal model, in which the pathologies of liver diseases are similar to man. This study further promotes the implementation of canine models in MSC-based treatments of liver diseases. L-MSCs were characterized and compared to BM-MSCs from the same individual. Both cell types demonstrated a spindle-shaped fibroblast-like morphology, possessed the same growth potential, and demonstrated similar immunomodulation gene expression of CD274, PTGS-1, and PTGS-2. Marked differences in cell surface markers, CD105 and CD146, distinguished these two cell populations, and L-MSCs retained a liver-specific imprinting, observed by expression of CK18 and CK19. Finally, both populations differentiated toward the osteogenic and adipogenic lineage; however, L-MSCs failed to differentiate into the chondrogenic lineage. In conclusion, characterization of canine L-MSCs and BM-MSCs demonstrated that the two cell type populations are highly comparable. Although it is still unclear which cell source is preferred for clinical application in liver treatment strategies, this study provides a foundation for future controlled studies with MSC therapy in various liver diseases in dogs before their application in man.
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