Department of Regenerative Medicine, Cell and Tissue Bank, Chair of Urology, Nicolaus Copernicus University in Torun, Ludwik Rydygier Medical College in Bydgoszcz, 85-094, Marii Sklodowskiej Curie 9 Street, 85-094, Bydgoszcz, Poland.
Stem Cell Res Ther. 2019 Jun 13;10(1):176. doi: 10.1186/s13287-019-1266-1.
Molecular mechanisms underlying the regenerative process induced by stem cells in tissue-engineered urinary bladder are poorly explained. The study was performed to explore the pathways associated with regeneration process in the urinary bladder reconstructed with adipose tissue-derived mesenchymal stromal cells (ASCs).
Rat urinary bladders were reconstructed with bladder acellular matrix (BAM) (n = 52) or BAM seeded with adipose tissue-derived mesenchymal stromal cells (ASCs) (n = 52). The process of bladder healing was analyzed at 7, 30, 90, and 180 days postoperatively using macroscopic histologic and molecular techniques. Gene expression was analyzed by microarrays and confirmed by real-time PCR.
Numerous differentially expressed genes (DEGs) were identified between the bladders augmented with BAM seeded with ASCs or BAM only. Pathway analysis of DEGs allows to discover numerous pathways among them Hedgehog, TGF-β, Jak-STAT, PI3-Akt, and Hippo modulated by ASCs during the healing process of tissue-engineered urinary bladder. Real-time PCR analysis confirmed upregulation of genes involved in the Hedgehog signaling pathway including Shh, Gli1, Smo, Bmp2, Bmp4, Wnt2, Wnt2b, Wnt4, Wnt5a, and Wnt10 in urinary bladders reconstructed with ASC-seeded grafts.
The study provided the unequivocal evidence that ASCs change the molecular pattern of healing in tissue-engineered urinary bladder and indicated which signaling pathways triggered by ASCs can be associated with the regenerative process. These pathways can be used as targets in the future studies on induced urinary bladder regeneration. Of particular interest is the Hedgehog signaling pathway that has been upregulated by ASCs during healing of tissue-engineered urinary bladder.
干细胞在组织工程化膀胱中诱导再生过程的分子机制尚未得到充分阐释。本研究旨在探讨脂肪组织来源间充质基质细胞（ASCs）构建的组织工程化膀胱中与再生过程相关的信号通路。
使用膀胱去细胞基质（BAM）（n=52）或 BAM 种植脂肪组织来源间充质基质细胞（ASCs）（n=52）构建大鼠膀胱。术后第 7、30、90 和 180 天，通过宏观组织学和分子技术分析膀胱愈合过程。通过微阵列分析基因表达，并通过实时 PCR 进行验证。
在仅用 BAM 或 BAM 种植 ASC 构建的膀胱中，鉴定出大量差异表达基因（DEGs）。对 DEGs 的通路分析发现，在组织工程化膀胱的愈合过程中，Hedgehog、TGF-β、Jak-STAT、PI3-Akt 和 Hippo 等多个信号通路受到 ASC 的调节。实时 PCR 分析证实，在 ASC 种植的移植物构建的膀胱中，Hedgehog 信号通路中 Shh、Gli1、Smo、Bmp2、Bmp4、Wnt2、Wnt2b、Wnt4、Wnt5a 和 Wnt10 等基因的表达上调。
本研究提供了明确的证据表明，ASCs 改变了组织工程化膀胱中愈合的分子模式，并指出了 ASC 触发的哪些信号通路可能与再生过程相关。这些通路可以作为未来诱导性膀胱再生研究的靶点。特别值得关注的是 Hedgehog 信号通路，它在组织工程化膀胱的愈合过程中被 ASC 上调。
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