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Disc-Derived Induced Pluripotent Stem Cells and Environmental Cues for Nucleus Pulposus Regeneration

ABSTRACT: Notochordal cells (NCs) are linked to a healthy state of the nucleus pulposus (NP) and are therefore considered a promising candidate for cell-based regenerative therapies. However, NCs are scarcely available as they are lost early in life, and attempts at in vitro expansion have failed because NCs lose their specific phenotype. The generation of notochordal-like cells (NLCs) from human induced pluripotent stem cells (hiPSCs) is considered a viable alternative. Therefore, this study aimed to build on the instructive capacity of decellularized notochordal cell-derived matrix (dNCM) and the epigenetic memory of tissue-specific hiPSCs derived from TIE2+ nucleus pulposus-progenitor cells (NPPCs) to improve hiPSC differentiation towards mature, healthy matrix-producing NLCs. As a comparison, donor-matched minimally invasive peripheral blood mononuclear cell (PBMC)-derived hiPSCs were generated. The results showed that the use of tissue-specific derived hiPSCs instructed by a mix of natural cues provided by dNCM allowed for an improved differentiation capacity, indicated by the increased expression of key phenotypic and functional NC/NPC markers. Additionally, within this in vitro environment, the cell-source influenced off-target differentiation resulting in increased neural- and immune-cell fate for the PBMC-derived hiPSC lines. In the end, Understanding how in vivo microenvironmental cues will direct differentiation and maturation of the hMEPCs is imperative to refine the differentiation protocol also taking into account the hiPSC-derived NLC functionality and survival within the challenging environment of the intervertebral disc.

ORGANISM(S): Homo sapiens

PROVIDER: GSE273124 | GEO | 2025/11/24

REPOSITORIES: GEO

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Project description:Objective: Aging and early degeneration of the intervertebral disc (IVD) involves the substition of notochordal cells (NCs) in the nucleus pulposus (NP) by chondrocyte-like cells (CLCs). This study investigated the gene expression profiles involved in this process using NP tissue from both non-chondrodystrophic and chondrodystrophic dogs, a species with naturally occuring IVD degeneration. Methods: Dual channel DNA microarrays were used to compare 1) healthy NP tissue, 2) NP tissue with a mixed population of NCs and CLCs, and 3) NP tissue containing solely CLCs. Canonical Wnt-signaling was validated using qPCR of relevant Wnt target genes. Caveolin-1, a known regulator of canonical Wnt signaling, was investigated further in tissue sections using qPCR and immunohistochemistry, and in cultured NCs by qPCR and immunofluorescence. Also, the NP of 3-month-old caveolin-1 knock-out mice was histopathologically evaluated and compared with wild type mice of the same age. Results: Early IVD degeneration involved significant regulations in numerous pathways, such as extracellular matrix remodeling, Bone Morphogenetic Protein- , and Wnt/beta-catenin-signaling. With regard to Wnt/beta-catenin signaling, axin2 gene expression was significantly higher in chondrodystrophic dogs compared with non-chondrodystrophic dogs. IVD degeneration involved significant downregulation of axin2 gene expression and caveolin-1 gene and protein expression. NCs showed abundant caveolin-1 expression in vivo and in vitro, whereas CLCs did not. The NP of 3-month-old WT mice were rich in viable NCs, whereas the NPs of 3-month-old caveolin-1 knock-out mice contained chondroid-like matrix with small, rounded cells, the majority of which showed morphological signs of apoptosis. Conclusions: Aging and the onset of degeneration of the IVD involve significant downregulation of canonical Wnt signaling and caveolin-1, which appears to be essential in the physiology and preservation of NCs. DNA microarrays were used to compare nucleus palposus (NP) tissue of healthy and chondrodystrophic individuals. Furthermore, the situation of the tissue was divided into three stages: NCR: notochordal cell(NC) rich; CR: tissue containing solely chondrocyte-like-cells (CLC) and T: tissue with a mixed population of NCs and CLCs. Comparisons were analysed on a 2-color platform against a common reference sample, consisting of a multitude of canine organs, including liver, spleen, kidney, lung, hart, intestine and bone.

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Disc-Derived Induced Pluripotent Stem Cells and Environmental Cues for Nucleus Pulposus Regeneration

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