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Mechanical stretching boosts expansion and regeneration of intestinal organoids through fueling stem cell self-renewal.

ABSTRACT: Intestinal organoids, derived from intestinal stem cell self-organization, recapitulate the tissue structures and behaviors of the intestinal epithelium, which hold great potential for the study of developmental biology, disease modeling, and regenerative medicine. The intestinal epithelium is exposed to dynamic mechanical forces which exert profound effects on gut development. However, the conventional intestinal organoid culture system neglects the key role of mechanical microenvironments but relies solely on biological factors. Here, we show that adding cyclic stretch to intestinal organoid cultures remarkably up-regulates the signature gene expression and proliferation of intestinal stem cells. Furthermore, mechanical stretching stimulates the expansion of SOX9⁺ progenitors by activating the Wnt/β-Catenin signaling. These data demonstrate that the incorporation of mechanical stretch boosts the stemness of intestinal stem cells, thus benefiting organoid growth. Our findings have provided a way to optimize an organoid generation system through understanding cross-talk between biological and mechanical factors, paving the way for the application of mechanical forces in organoid-based models.

SUBMITTER: Meng F

PROVIDER: S-EPMC9626719 | biostudies-literature | 2022 Nov

REPOSITORIES: biostudies-literature

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Mechanical stretching boosts expansion and regeneration of intestinal organoids through fueling stem cell self-renewal.

Meng Fanlu F Shen Congcong C Yang Li L Ni Chao C Huang Jianyong J Lin Kaijun K Cao Zanxia Z Xu Shicai S Cui Wanling W Wang Xiaoxin X Zhou Bailing B Xiong Chunyang C Wang Jihua J Zhao Bing B

Cell regeneration (London, England) 20221102 1

Intestinal organoids, derived from intestinal stem cell self-organization, recapitulate the tissue structures and behaviors of the intestinal epithelium, which hold great potential for the study of developmental biology, disease modeling, and regenerative medicine. The intestinal epithelium is exposed to dynamic mechanical forces which exert profound effects on gut development. However, the conventional intestinal organoid culture system neglects the key role of mechanical microenvironments but ...[more]

PMID: 36319799

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Project description:UnlabelledSkin tissue expansion is a clinical procedure for skin regeneration to reconstruct cutaneous defects that can be accompanied by severe complications. The transplantation of mesenchymal stem cells (MSCs) has been proven effective in promoting skin expansion and helping to ameliorate complications; however, systematic understanding of its mechanism remains unclear. MSCs from luciferase-Tg Lewis rats were intravenously transplanted into a rat tissue expansion model to identify homing and transdifferentiation. To clarify underlying mechanisms, a systematic approach was used to identify the differentially expressed genes between mechanically stretched human MSCs and controls. The biological significance of these changes was analyzed through bioinformatic methods. We further investigated genes and pathways of interest to disclose their potential role in mechanical stretching-induced skin regeneration. Cross sections of skin samples from the expanded group showed significantly more luciferase(+) and stromal cell-derived factor 1α (SDF-1α)(+), luciferase(+)keratin 14(+), and luciferase(+)CD31(+) cells than the control group, indicating MSC transdifferentiation into epidermal basal cells and endothelial cells after SDF-1α-mediated homing. Microarray analysis suggested upregulation of genes related to hypoxia, vascularization, and cell proliferation in the stretched human MSCs. Further investigation showed that the homing of MSCs was blocked by short interfering RNA targeted against matrix metalloproteinase 2, and that mechanical stretching-induced vascular endothelial growth factor A upregulation was related to the Janus kinase/signal transducer and activator of transcription (Jak-STAT) and Wnt signaling pathways. This study determines that mechanical stretching might promote skin regeneration by upregulating MSC expression of genes related to hypoxia, vascularization, and cell proliferation; enhancing transplanted MSC homing to the expanded skin; and transdifferentiation into epidermal basal cells and endothelial cells.SignificanceSkin tissue expansion is a clinical procedure for skin regeneration to cover cutaneous defects that can be accompanied by severe complications. The transplantation of mesenchymal stem cells (MSCs) has been proven effective in promoting skin expansion and ameliorating complications. This study, which sought to provide a systematic understanding of the mechanism, determined that mechanical stretching could upregulate MSC expression of genes related to hypoxia, vascularization, and cell proliferation; enhance transplanted MSC homing to the expanded skin tissue; and promote their transdifferentiation into epidermal basal cells and endothelial cells.

Dataset Information

Mechanical stretching boosts expansion and regeneration of intestinal organoids through fueling stem cell self-renewal.

Publications

Mechanical stretching boosts expansion and regeneration of intestinal organoids through fueling stem cell self-renewal.

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