SummaryIn vitro and in vivo studies evidenced that mesenchymal stem cells (MSCs) contribute to intervertebral disc (IVD) regeneration by differentiation towards the disc phenotype and matrix synthesis and/or by paracrine signalling to endogenous cells, thereby promoting a healthier disc phenotype in degenerative discs. The aim of this study was to investigate IVD response to human MSC (hMSC) treatment based on the disc degenerative state and hMSC carrier. Bovine caudal IVDs with endplates were cultured in a bioreactor under simulated physiological (0.1 Hz load and sufficient glucose) or degenerative (10 Hz load and limited glucose) conditions for 7 days. Discs were partially nucleotomised, restored with hMSCs in either fibrin gel or saline solution and cultured under physiological conditions for 7 days. Controls included fibrin and saline without hMSCs. Cell viability, histology, disc height, and gene expression analyses were performed to evaluate regeneration. hMSCs in fibrin were viable and homogenously distributed following 7 days of culture under dynamic loading in partially nucleotomised discs. IVD response to hMSCs was conditioned by both disc degenerative state and hMSC carrier. The effect of the regenerative treatment was stronger on simulated-degenerative discs than on simulated-physiological discs. hMSCs in fibrin induced a superior anabolic response in degenerative IVDs compared with fibrin alone, thus suggesting an added value of the cellular therapy compared with an acellular solution. When comparing fibrin and saline as a hMSC carrier, a significantly higher anabolic response was observed in IVDs treated with hMSCs in fibrin. Moreover, it was found that the degenerative state of the disc influenced hMSC differentiation. Indeed, a significantly higher expression of specific discogenic markers (ACAN and CA12) was observed in hMSCs implanted into physiological discs than in those implanted into degenerative discs. In conclusion, host disc cells and donor hMSC response depend on the degenerative state of the host disc and carrier used for hMSC delivery, and these two aspects need to be considered for a successful translation of hMSC therapies for the treatment of IVD degeneration.

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