肾脏类器官的构建及其应用

Construction of kidney organoid and its application

摘要

肾移植是终末期肾病的重要治疗方式，但其长期疗效仍受供肾短缺、供肾质量下降、缺血-再灌注损伤、排斥反应和慢性移植物失功等因素限制。传统监测手段在灵敏度、特异度和动态评估方面存在不足，亟需建立更接近人肾脏发育、结构和功能特征的新型研究模型。肾脏类器官是由干细胞或祖细胞在三维培养条件下形成的器官样结构，广义上包括诱导多能干细胞（iPSC）来源肾脏类器官以及成体或原代来源肾小管类器官。本文重点围绕iPSC来源肾脏类器官展开，系统概述其定义、发展历程及在肾脏发育机制研究、遗传性和获得性肾病建模、药物筛选与肾毒性评价、精准医学研究中的应用。近年来，随着诱导分化体系、祖细胞扩增、血管化工程、收集系统整合和空间组装策略的不断发展，肾脏类器官在器官移植领域显示出重要潜力，可用于移植免疫机制研究、排斥反应模拟、移植后疾病复发风险评估、供肾离体修复和常温机械灌注递送等转化前研究。现阶段，肾脏类器官尚不能替代整肾移植，其临床转化仍受成熟度不足、血管整合有限、尿液引流通路不完善、异位分化及长期安全性不确定等因素制约。未来，构建同时具备稳定血管化、持续滤过、有效引流和宿主长期功能整合能力的工程化肾组织，将是推动肾脏类器官从基础研究迈向移植转化应用的关键方向。

Abstract

Kidney transplantation is an important treatment method for end-stage renal disease, but its long-term efficacy is still limited by factors such as shortage of donor kidneys, decline in donor kidney quality, ischemia-reperfusion injury, rejection reactions and chronic graft failure. Traditional monitoring methods have deficiencies in sensitivity, specificity and dynamic assessment, and there is an urgent need to establish new research models that are closer to the development, structure and functional characteristics of human kidneys. Kidney organoids are organ-like structures formed by stem cells or progenitor cells under three-dimensional culture conditions. Broadly speaking, they include kidney organoids derived from induced pluripotent stem cell (iPSC) and renal tubule organoids from adult or primary sources. This article focuses on iPSC-derived kidney organoids and systematically summarizes their definition, development history and applications in the study of kidney development mechanisms, modeling of hereditary and acquired kidney diseases, drug screening and evaluation of renal toxicity, and precision medicine research. In recent years, with the continuous development of induction differentiation systems, progenitor cell expansion, vascularization engineering, collection system integration and spatial assembly strategies, kidney organoids have shown significant potential in the field of organ transplantation and can be used for pre-translation research such as study of transplantation immune mechanisms, simulation of rejection, assessment of recurrence risk after transplantation, in vitro repair of donor kidneys and normothermic mechanical perfusion delivery. Currently, kidney organoids cannot replace whole kidney transplantation, and their clinical translation is still constrained by factors such as insufficient maturity, limited vascular integration, incomplete urine drainage pathways, ectopic differentiation and uncertainty of long-term safety. In the future, constructing engineered kidney tissues with stable vascularization, continuous filtration, effective drainage and long-term host functional integration capabilities will be a key direction for promoting kidney organoids from basic research to transplantation transformation applications.

关键词

肾脏类器官 / 肾移植 / 诱导多能干细胞 / 肾小管类器官 / 移植免疫 / 血管化 / 供肾修复 / 再生医学

Key words

Kidney organoid / Kidney transplantation / Induced pluripotent stem cell / Kidney tubular organoid / Transplantation immunity / Vascularization / Donor kidney repair / Regenerative medicine

参考文献

[1] HUNTER J, HOSGOOD S, MOERS C, et al. Improving outcomes in kidney transplantation through advances in donor organ perfusion[J]. Nat Rev Nephrol, 2025, 21(12): 818-832. DOI: 10.1038/s41581-025-00993-8.

[2] FLEETWOOD V A, LENTINE K L. Multifaceted innovations needed to advance transplant nephrology[J]. Nat Rev Nephrol, 2025, 21(2): 81-82. DOI: 10.1038/s41581-024-00924-z.

[3] WESTPHAL S G, MANNON R B. Biomarkers of rejection in kidney transplantation[J]. Am J Kidney Dis, 2025, 85(3): 364-374. DOI: 10.1053/j.ajkd.2024.07.018.

[4] MORIZANE R, LAM A Q, FREEDMAN B S, et al. Nephron organoids derived from human pluripotent stem cells model kidney development and injury[J]. Nat Biotechnol, 2015, 33(11): 1193-1200. DOI: 10.1038/nbt.3392.

[5] TAKASATO M, ER P X, CHIU H S, et al. Kidney organoids from human iPS cells contain multiple lineages and model human nephrogenesis[J]. Nature, 2015, 526(7574): 564-568. DOI: 10.1038/nature15695.

[6] SHANKAR A S, DU Z, MORA H T, et al. Human kidney organoids produce functional renin[J]. Kidney Int, 2021, 99(1): 134-147. DOI: 10.1016/j.kint.2020.08.008.

[7] TAGUCHI A, KAKU Y, OHMORI T, et al. Redefining the in vivo origin of metanephric nephron progenitors enables generation of complex kidney structures from pluripotent stem cells[J]. Cell Stem Cell, 2014, 14(1): 53-67. DOI: 10.1016/j.stem.2013.11.010.

[8] SUBRAMANIAN A, SIDHOM E H, EMANI M, et al. Single cell census of human kidney organoids shows reproducibility and diminished off-target cells after transplantation[J]. Nat Commun, 2019, 10: 5462. DOI: 10.1038/s41467-019-13382-0.

[9] WU H, UCHIMURA K, DONNELLY E L, et al. Comparative analysis and refinement of human PSC-derived kidney organoid differentiation with single-cell transcriptomics[J]. Cell Stem Cell, 2018, 23(6): 869-881.e8. DOI: 10.1016/j.stem.2018.10.010.

[10] 陶开山, 张玄, 宋俊伯. 生物智造器官移植的应用前景: 技术进展、临床挑战与未来展望[J]. 中华普通外科杂志, 2026, 41(3): 227-232. DOI: 10.3760/cma.j.cn113855-20260114-00036.

[11] TAO K S, ZHANG X, SONG J B . Prospects of biomanufactured organ transplantation: technological advances, clinical challenges, and future perspectives[J]. Chin J Gen Surg, 2026, 41(3): 227-232. DOI: 10.3760/cma.j.cn113855-20260114-00036.

[12] LOW J H, LI P, CHEW E G Y, et al. Generation of human PSC-derived kidney organoids with patterned nephron segments and a de novo vascular network[J]. Cell Stem Cell, 2019, 25(3): 373-387.e9. DOI: 10.1016/j.stem.2019.06.009.

[13] SCHUTGENS F, ROOKMAAKER M B, MARGARITIS T, et al. Tubuloids derived from human adult kidney and urine for personalized disease modeling[J]. Nat Biotechnol, 2019, 37(3): 303-313. DOI: 10.1038/s41587-019-0048-8.

[14] YOUSEF YENGEJ F A, JANSEN J, ROOKMAAKER M B, et al. Kidney organoids and tubuloids[J]. Cells, 2020, 9(6): 1326. DOI: 10.3390/cells9061326.

[15] VANSLAMBROUCK J M, TAN K S, MAH S, et al. Generation of proximal tubule-enhanced kidney organoids from human pluripotent stem cells[J]. Nat Protoc, 2023, 18(11): 3229-3252. DOI: 10.1038/s41596-023-00880-1.

[16] HUANG B, ZENG Z, KIM S, et al. Long-term expandable mouse and human-induced nephron progenitor cells enable kidney organoid maturation and modeling of plasticity and disease[J]. Cell Stem Cell, 2024, 31(6): 921-939.e17. DOI: 10.1016/j.stem.2024.04.002.

[17] PRZEPIORSKI A, SANDER V, TRAN T, et al. A simple bioreactor-based method to generate kidney organoids from pluripotent stem cells[J]. Stem Cell Rep, 2018, 11(2): 470-484. DOI: 10.1016/j.stemcr.2018.06.018.

[18] KUMAR S V, ER P X, LAWLOR K T, et al. Kidney micro-organoids in suspension culture as a scalable source of human pluripotent stem cell-derived kidney cells[J]. Development, 2019, 146(5): dev172361. DOI: 10.1242/dev.172361.

[19] VANSLAMBROUCK J M, WILSON S B, TAN K S, et al. Enhanced metanephric specification to functional proximal tubule enables toxicity screening and infectious disease modelling in kidney organoids[J]. Nat Commun, 2022, 13: 5943. DOI: 10.1038/s41467-022-33623-z.

[20] SCHNELL J, MIAO Z, ACHIENG M, et al. Controlling nephron precursor differentiation to generate proximal-biased kidney organoids with emerging maturity[J]. Nat Commun, 2025, 16: 8136. DOI: 10.1038/s41467-025-63107-9.

[21] FREEDMAN B S, BROOKS C R, LAM A Q, et al. Modelling kidney disease with CRISPR-mutant kidney organoids derived from human pluripotent epiblast spheroids[J]. Nat Commun, 2015, 6: 8715. DOI: 10.1038/ncomms9715.

[22] OHMORI T, DE S, TANIGAWA S, et al. Impaired NEPHRIN localization in kidney organoids derived from nephrotic patient iPS cells[J]. Sci Rep, 2021, 11: 3982. DOI: 10.1038/s41598-021-83501-9.

[23] CRUZ N M, SONG X, CZERNIECKI S M, et al. Organoid cystogenesis reveals a critical role of microenvironment in human polycystic kidney disease[J]. Nat Mater, 2017, 16(11): 1112-1119. DOI: 10.1038/nmat4994.

[24] XU Y, KUPPE C, PERALES-PATN J, et al. Adult human kidney organoids originate from CD24⁺ cells and represent an advanced model for adult polycystic kidney disease [J]. Nat Genet, 2022, 54(11): 1690-1701. DOI: 10.1038/s41588-022-01202-z.

[25] CRUZ N M, REDDY R, MCFALINE-FIGUEROA J L, et al. Modelling ciliopathy phenotypes in human tissues derived from pluripotent stem cells with genetically ablated cilia[J]. Nat Biomed Eng, 2022, 6(4): 463-475. DOI: 10.1038/s41551-022-00880-8.

[26] SONG H, DUMAS S J, WANG G, et al. APOL1 risk variants induce metabolic reprogramming of podocytes in patient-derived kidney organoids[J]. Stem Cell Reports, 2025, 20(10): 102650. DOI: 10.1016/j.stemcr.2025.102650.

[27] JANSEN J, REIMER K C, NAGAI J S, et al. SARS-CoV-2 infects the human kidney and drives fibrosis in kidney organoids[J]. Cell Stem Cell, 2022, 29(2): 217-231.e8. DOI: 10.1016/j.stem.2021.12.010.

[28] VANSLAMBROUCK J M, NEIL J A, RUDRARAJU R, et al. Kidney organoids reveal redundancy in viral entry pathways during ACE2-dependent SARS-CoV-2 infection[J]. J Virol, 2024, 98(3): e01802-e01823. DOI: 10.1128/jvi.01802-23.

[29] LITTLE M H, WILSON S B. Advances and continuing challenges in differentiation of stem cells to human kidney tissue[J]. Nat Rev Nephrol, 2026, 22(2): 122-136. DOI: 10.1038/s41581-025-01018-0.

[30] VAN DEN BERG C W, DUMAS S J, LITTLE M H, et al. Challenges in maturation and integration of kidney organoids for stem cell-based renal replacement therapy[J]. Kidney Int, 2025, 107(2): 262-270. DOI: 10.1016/j.kint.2024.10.028.

[31] KONING M, DUMAS S J, AVRAMUT M C, et al. Vasculogenesis in kidney organoids upon transplantation[J]. npj Regen Med, 2022, 7: 40. DOI: 10.1038/s41536-022-00237-4.

[32] HOMAN K A, GUPTA N, KROLL K T, et al. Flow-enhanced vascularization and maturation of kidney organoids in vitro[J]. Nat Meth, 2019, 16(3): 255-262. DOI: 10.1038/s41592-019-0325-y.

[33] VAN DEN BERG C W, RITSMA L, AVRAMUT M C, et al. Renal subcapsular transplantation of PSC-derived kidney organoids induces neo-vasculogenesis and significant glomerular and tubular maturation in vivo[J]. Stem Cell Rep, 2018, 10(3): 751-765. DOI: 10.1016/j.stemcr.2018.01.041.

[34] MAGGIORE J C, LEGRAW R, PRZEPIORSKI A, et al. A genetically inducible endothelial niche enables vascularization of human kidney organoids with multilineage maturation and emergence of renin expressing cells[J]. Kidney Int, 2024, 106(6): 1086-1100. DOI: 10.1016/j.kint.2024.05.026.

[35] TEKGUC M, MATSUMOTO T, ALTENBURGER L M, et al. Engineering scalable vascularized kidney organoids for in vivo glomerular filtration with human endothelial integration[J]. NPJ Biomed Innov, 2026, 3(1): 10. DOI: 10.1038/s44385-025-00063-5.

[36] SHI M, CROUSE B, SUNDARAM N, et al. Integrating collecting systems in human kidney organoids through fusion of distal nephron to ureteric bud[J]. Cell Stem Cell, 2025, 32(7): 1055-1070.e8. DOI: 10.1016/j.stem.2025.04.008.

[37] HUANG B, MEDINA P, HE J, et al. Spatially patterned kidney assembloids recapitulate progenitor self-assembly and enable high-fidelity in vivo disease modeling[J]. Cell Stem Cell, 2025, 32(10): 1614-1633.e13. DOI: 10.1016/j.stem.2025.08.013.

[38] MEDINA P, HUANG B, ZHANG C, et al. Assembly of a functionally mature synthetic kidney organoid with spatial patterning from the self-organization of expandable kidney progenitors: TH-PO395[J]. J Am Soc Nephrol, 2024, 35(10S): 1. DOI: 10.1681/asn.2024mwc0eq3m.

[39] MON-WEI YU S, CHOI J Y, KADY J, et al. Transplantation of human kidney organoids elicited a robust allogeneic response in a humanized mouse model[J]. Kidney Int, 2025, 107(6): 1011-1016. DOI: 10.1016/j.kint.2025.02.027.

[40] GUPTA A K, MINOCHA E, KOSS K M, et al. A kidney organoid-based readout to assess disease activity in primary and recurrent focal segmental glomerulosclerosis[J]. Kidney Int, 2025, 107(5): 888-902. DOI: 10.1016/j.kint.2025.01.018.

[41] GARRETA E, MOYA-RULL D, CENTENO A, et al. Systematic production of human kidney organoids for transplantation in porcine kidneys during ex vivo machine perfusion[J]. Nat Biomed Eng, 2025: 1-18. DOI: 10.1038/s41551-025-01542-1.

基金资助

国家自然科学基金面上项目(82470778)

广东省器官医学重点实验室基金(2023B1212060020)

云南省科技计划基础研究专项重点项目(202501AS070169)

中山大学-华越生物人工肾脏与肾脏再生研究实验室联合基金(SYSU-50000-20240428-0001)