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Obesity hinders the efficacy of adipose-derived stem cells for knee osteoarthritis by reducing the proportion of DPP4+ stem cells

ABSTRACT: Osteoarthritis (OA) is the most prevalent and disabling joint disease, while adipose-derived stem cells (ASCs) have emerged as a promising therapeutic option in pre-clinical studies. However, the therapeutic efficacy of ASCs may be influenced by the source of these cells, especially in obese patients. This study compared the effects of intra-articular injections of ASCs from wild-type (WT) and ob/ob (OB) mice. Behavioral and histological analyses demonstrated that WT-ASCs significantly alleviated OA symptoms, restoring paw withdrawal thresholds and improving gait parameters while reducing cartilage degradation. In contrast, OB-ASCs only partially improved gait and did not significantly affect cartilage degeneration. Single-cell RNA sequencing of stromal vascular fractions from subcutaneous adipose tissue revealed distinct ASC subpopulations, with DPP4+ cells being notably reduced in obese mice. In vitro, OB-ASCs and high-fat-diet (HFD)-ASCs exhibited impaired proliferation and chondrogenesis but HFD-ASCs retained anti-inflammatory properties. Further investigation using fluorescence-activated cell sorting (FACS) isolated DPP4+ and DPP4- ASCs from WT mice, demonstrating that DPP4+ cells had superior chondrogenic potential and reduced OA pain more effectively than DPP4- cells. These findings suggest that obesity impairs the therapeutic potential of ASCs in OA, primarily due to reduced proliferation and chondrogenesis, and highlight DPP4+ ASCs as a promising candidate for cell therapy in OA.

ORGANISM(S): Mus musculus

PROVIDER: GSE291456 | GEO | 2025/03/16

REPOSITORIES: GEO

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Project description:To reveal the organisation of the cartilage cell chondrocyte genome and identify changes that occur within this organisation during development and due to osteoarthritis (OA). Methods Assay for Transposase -Accessible Chromatin using Sequencing (ATAC-seq) was performed on chondrocytes isolated from 16 patients undergoing total hip replacement because of OA (n=7) or due to a neck of femur fracture (NOF, n=9). ATAC-seq was similarly performed on bone-marrow mesenchymal stem cells (BM-MSC) and differentiated chondrocytes of two donors. DNA sequence reads (av. 50 million/sample) were aligned to human genome Hg38. Peaks were called using MACS2 and differential accessibility identified by DiffBind. Interexperiment comparisons and intersection with published gene expression changes, chondrogenesis ChIP-seq, knee ATAC-seq and human tissue scATAC-seq were performed in Galaxy and R. OA GWAS signal regions were overlapped with our defined chondrocyte ATAC-seq peaks. Results In BM-MSC and derived chondrocytes we mapped 138005 open chromatin regions, of which 20979 and 50699 significantly increased and decreased respectively during cell differentiation. In hip chondrocytes we identified 115295 open chromatin regions, 1383 and 573 were more or less differentially accessible respectively when comparing OA with NOF samples. In both data sets ‘newly accessible regions were enriched at enhancer regions (defined by ChIP-seq). Comparing the data with the ATAC-seq from the single cell ATLAS we identified 11866 open regions exclusive to chondrocytes. Genes associated with these regions were significantly enriched for cartilage-related gene ontology terms. Taking the 420 OA GWAS signals present in the GWAS catalogue, 313 of the OA regions (defined as lead SNP + proxy SNPs with r2 ≥ 0.8) overlapped with a chondrocyte ATAC-seq region. Conclusions Here we have mapped chromatin accessible region changes during chondrogenesis, showing that newly accessible regions are enriched at enhancer regions and positively correlate with gene expression. Open chromatin region changes between OA and NOF cartilage were fewer, and peak differences were subtle. Overall, we have associated OA GWAS loci with accessible regions and defined regions of the genome specific to cartilage and chondrogenesis.

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Obesity hinders the efficacy of adipose-derived stem cells for knee osteoarthritis by reducing the proportion of DPP4+ stem cells

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