肾脏脱细胞细胞外基质增强人肾脏类器官的血管化和成熟,Advanced Science

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肾脏脱细胞细胞外基质增强人肾脏类器官的血管化和成熟
Advanced Science ( IF 14.3 ) Pub Date : 2022-03-24 , DOI: 10.1002/advs.202103526
Jin Won Kim ₁ , Sun Ah Nam ₁ , Jawoon Yi ₂ , Jae Yun Kim ₃ , Jong Young Lee ₁ , Seo-Yeon Park ₁ , Tugce Sen ₄ , Yoo-Mi Choi ₅ , Jae Yeon Lee ₆ , Hong Lim Kim ₇ , Hyung Wook Kim ₈ , Jiwhan Park ₂ , Dong-Woo Cho _{3,

4} , Yong Kyun Kim _{1,

8}

Affiliation

源自人类多能干细胞 (hPSC) 的肾脏类器官在疾病建模和再生医学方面具有广泛的潜力。然而，肾脏类器官的有限血管化和不成熟仍有待克服。细胞外基质（ECM）可以为细胞生长和分化提供机械支持和生化微环境。本文报道了使用肾脏去细胞细胞外基质 (dECM) 水凝胶培养具有广泛血管网络和自身内皮细胞的 hPSC 衍生的肾脏类器官的体外方法。单细胞转录组学表明，与不使用肾脏 dECM 培养的相比，使用肾脏 dECM 培养的血管化肾脏类器官具有更成熟的肾小球发育模式，并且与人肾脏的相似性更高。分化α-半乳糖苷酶 A (GLA)-通过使用肾脏 dECM 的培养方法将使用 CRISPR/Cas9 生成的 hPSC 敲除到肾脏类器官中，有效地概括了法布里肾病和血管病变。将具有肾脏 dECM 的肾脏类器官移植到小鼠肾脏中，可以加速从宿主小鼠肾脏募集内皮细胞，并通过比没有肾脏 dECM 的那些更有组织的裂隙隔膜状结构来维持血管完整性。用于诱导肾脏器官广泛血管化和成熟的肾脏 dECM 方法可应用于肾脏发育、疾病建模和再生医学的研究。

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Kidney Decellularized Extracellular Matrix Enhanced the Vascularization and Maturation of Human Kidney Organoids

Kidney organoids derived from human pluripotent stem cells (hPSCs) have extensive potential for disease modelling and regenerative medicine. However, the limited vascularization and immaturity of kidney organoids have been still remained to overcome. Extracellular matrix (ECM) can provide mechanical support and a biochemical microenvironment for cell growth and differentiation. Here in vitro methods using a kidney decellularized extracellular matrix (dECM) hydrogel to culture hPSC-derived kidney organoids, which have extensive vascular network and their own endothelial cells, are reported. Single-cell transcriptomics reveal that the vascularized kidney organoids cultured using the kidney dECM have more mature patterns of glomerular development and higher similarity to human kidney than those cultured without the kidney dECM. Differentiation of α-galactosidase A (GLA)-knock-out hPSCs generated using CRISPR/Cas9 into kidney organoids by the culture method using kidney dECM efficiently recapitulate Fabry nephropathy with vasculopathy. Transplantation of kidney organoids with kidney dECM into kidney of mouse accelerates the recruitment of endothelial cells from the host mouse kidney and maintains vascular integrity with the more organized slit diaphragm-like structures than those without kidney dECM. The kidney dECM methodology for inducing extensive vascularization and maturation of kidney organoids can be applied to studies for kidney development, disease modeling, and regenerative medicine.

更新日期：2022-03-24

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