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An advanced ADSC therapy for keloid prevention using identification of functional subgroups by single cell transcriptomic analysis

ABSTRACT: The clinical treatments for keloids are poor efficacy,There is evidence forADSCs acting as a physiological response to local injury or as rejuvenating mechanisms.But the use of exogenous ADSCs fulfill the general accepted criteria for cell-based therapies, but still need further investigations into their efficiency. In this study, we firstly employed microarray techniques and bioinformatics analysis to screen for whole transcriptome differences involved in keloids, enabling the identification of DEGs and functional molecular associated with keloids mechanism. Secondly, we developed functional clustering of stem cells and marker genes of each cluster through single cell sequencing of ADSCs from healthy adults and pigs by bioinformatics analysis. Finally, we identified ADSC subpopulations with KK and KF therapeutic potential, respectively. anti-fibrotic transcriptomic identification and quantitative clustering was performed, and the function of specific ADSCs cluster was investigated in the hypertrophic scar prophylaxis using the miniature pig model. This study might open the way to a new era of mesenchymal stem cells in the treatment of keloids for promising therapeutic advancements.

ORGANISM(S): Sus scrofa

PROVIDER: GSE233884 | GEO | 2023/06/24

REPOSITORIES: GEO

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Project description:Adipogenesis occurs through a specific gene program in undifferentiated fat progenitors. We hypothesized that the properties of the fat progenitors are regulated by hox genes, the developmental genes essential in different tissue stem cells. Their biased expression in white and brown fat implies roles in distinguishing the two fat types. Among 39 Hox genes, Hoxc8 is highly enriched in undifferentiated adipose tissue stem cells (ADSCs) and down-regulated in differentiated adipocytes. Forced expression of Hoxc8 suppressed adipocyte differentiation of ADSCs. Using microarrays, we investigated the effect of Hoxc8 overexpression on global transcripts in ADSCs. We compared among four groups: untreated ADSCs, adipogenic induction media (MDI)-treated ADSCs, MDI-treated ADSC-vector and MDI-treated ADSC-Hoxc8. A number of, but not all, adipogenesis-related genes are suppressed by Hoxc8. This dataset illustrates the global effect of Hoxc8, a developmental transcription factor, on the expression of adipogenesis-related genes. Gene expression was compared among untreated ADSCs (control), adipogenic induction media-treated ADSCs, adipogenic induction media-treated ADSC-vector (ADSCs transduced with control vector), and adipogenic induction media-treated ADSC-Hoxc8 (ADSCs transduced with human Hoxc8). Total RNA was isolated from ADSCs using the Qiagen RNeasy kit (Qiagen). At NimbleGen, quality and yield were verified before cDNA synthesis and Cy3-end labeling. The labeled cDNA samples were hybridized to Homo sapiens 4-Plex arrays (Roche NimbleGen, A4487001-00-01) that represent 24,000 human genes. Raw data files for each sample were normalized and background-corrected using a Robust Multi-Array Analysis as implemented by NimbleScan software. Students’ two-tail t-tests were conducted among the samples for each transcript and fold-change was determined. Transcripts whose abundance was significantly altered (P < 0.05) and an absolute fold change greater than 2 were defined as differentially regulated.

Project description:Bone tissue engineering is considered the optimal solution for the repair of large bone defects. Previous studies by our team have demonstrated the effectiveness of a "bottom-up" microtissue engineering strategy using bone marrow mesenchymal stem cells (BMSCs) to improve the utilization efficiency of seed cells. However, this strategy requires the extraction of bone marrow, which is associated with significant trauma and difficulties in obtaining the cells. Adipose-derived mesenchymal stem cells (ADSCs), obtained from aspirated adipose tissue, offer a less invasive and more accessible alternative, but their osteogenic capacity is noticeably weaker, severely limiting their application as seed cells in bone tissue engineering repair.Cell-free fat extract (CEFFE) is a cell-free liquid component extracted from adipose tissue, which exhibits beneficial properties such as promoting proliferation, antioxidation, anti-apoptosis, and angiogenesis. In this study, during the preparation of ADSC-based osteogenic microtissues, we first discovered that CEFFE significantly enhanced the osteogenic activity of ADSCs. Furthermore, we observed the formation of dense osteogenic membranes as early as day 7 of osteogenic induction. When the microtissues based on CEFFE-treated ADSCs were implanted subcutaneously in nude mice, we found a significant enhancement in their osteogenic activity. Finally, to further investigate the mechanism underlying the enhancement of ADSC osteogenic differentiation by CEFFE, we performed transcriptomic analysis of CEFFE-treated ADSCs and validated the activation of the key PI3K-Akt pathway using Western blotting.In conclusion, this study presents a novel approach for the preparation of ADSC-based osteogenic microtissues using CEFFE and provides insights into the mechanisms underlying the enhancement of osteogenic activity. These findings hold significant implications for the field of bone tissue engineering and offer potential advancements in the clinical translation of ADSC-based therapies.

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An advanced ADSC therapy for keloid prevention using identification of functional subgroups by single cell transcriptomic analysis

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