慢性肾脏病发病率较高，且1%的患者会发展成终末期肾病。目前，终末期肾病的临床干预手段有限，药物仅能延缓病情进展，无法修复受损的肾脏细胞和器官。肾移植和透析仍然是终末期肾病仅有的治疗选择。因此，构建有效的肾脏病防控体系，降低尿毒症发生率和病死率是全球公共卫生与健康面临的巨大挑战！
近年来，再生医学凭借其在医学领域的巨大潜力，受到了科学家们和政策的高度关注。随着研究的不断深入，再生医学在多个领域取得了显著的成果，为多种疾病的治疗带来了新的希望。因此，肾脏再生医学或可为解决肾脏病的防治难题提供重要思路。
肾脏再生医学概况
再生医学主要从以下几个方面进行研究，以实现人体损伤组织和器官的重建。（1）探究组织在正常状态下的发生和发育过程。（2）研究组织在受损情况下的自我修复和再生机制。（3）利用特定方法在体内增强组织的修复能力。（4）在体外构建模拟人体组织器官，用于机体移植。详见图1。
图1 肾脏再生医学新认识
肾脏的结构多样且功能复杂，因此，肾脏再生研究极具挑战性。好在，新兴技术的发展为肾脏再生医学研究提供了有力支持。（1）单细胞测序：带来高分辨率剖析正常发育和修复过程的能力的巨大变革。（2）诱导多能干细胞：使在体外不使用人类囊胚的情况下产生人类肾脏组织成为可能。（3）CRISPR/Cas9基因技术：应用于人类诱导多能干细胞技术，能够对这种干细胞衍生的人类肾脏组织进行完整地表征。
肾小管修复机制
（1）存活肾小管上皮细胞去分化
健康的肾小管由非增生的成熟上皮细胞组成，并表达分化标记物。在受到损伤后，上皮细胞会发生凋亡、坏死和脱落。存活的上皮细胞会经历去分化过程，获得增生的表型。这些存活的去分化细胞会重建肾单元的肾小管上皮。其中，大部分去分化细胞会再次分化，并下调去分化基因的表达。
（2）肾小管祖细胞再生
分散的肾小管上皮祖细胞表达CD24、CD133以及其他近端小管去分化的特征基因，如Vimentin和KIM-1。当受到损伤时，成熟的小管细胞会发生凋亡。随后，分散的肾小管祖细胞会在损伤后分裂增生，重新构建肾小管。再生后，小部分分散的肾小管祖细胞亚群得以保存。
基于干细胞的治疗
干细胞在再生医学研究中占据着重要的地位，其具备自我更新和多能分化的特性，根据增殖分化能力可分为成体干细胞、多潜能干细胞两大类（图2）。
图2 干细胞的分类
其中，间充质干细胞、肾脏干/祖细胞、诱导多能干细胞比较受关注。
（1）间充质干细胞
间充质干细胞在多种肾脏疾病中具有潜在治疗价值，如急性肾损伤、肾移植、慢性肾脏病。肾损伤后，趋化因子会促使间充质干细胞向病变部位迁移，并产生生长因子，从而协同肾脏干/祖细胞生成生长因子，促进细胞修复。此外，间充质干细胞通过全身血液循环及驻留免疫细胞调节免疫，抑制全身及局灶性炎症反应，可以一定程度减少肾脏的纤维化进程，有助于组织的再生修复。
在许多动物模型中，间充质干细胞已显示出其在改善急性肾损伤方面的有效性。自体输注间充质干细胞的患者在1年时表现出移植排斥反应减少和肾功能改善的趋势。
（2）肾脏祖细胞
欧美团队的临床研究表明，肾内注射自体肾小管作为一种创新的肾脏修复技术具有较好的安全性。临床试验使用终末分化的肾小管细胞群，其再生修复能力远弱于未成熟的肾小管祖细胞。研究显示，肾内移植尿源性SOX9+肾小管祖细胞有助于修复肾脏损伤。
（3）诱导多能干细胞
诱导多能干细胞可以治疗急性肾损伤、肾性贫血。研究显示，人诱导多能干细胞源性肾祖细胞治疗能够改善小鼠急性肾损伤的肾功能和病理状况；全身性的人诱导多能干细胞可以减轻急性肾损伤后的肾小管损伤，以及肾小管周围毛细血管稀疏的问题。
肾脏类器官的应用
肾脏类器官的应用领域主要包括以下几个方面。
（1）疾病模型
可用于构建遗传性肾病模型和环境相关的肾脏疾病模型等疾病模型。
（2）药物筛选
传统的体外模型存在一定局限性，如原代细胞生长能力有限，随时间推移易失去表型；动物模型则不仅成本高昂，还需要大量时间和专业知识，且涉及伦理问题，通常与人类系统相关性较低。相比之下，肾脏类器官对已知肾毒性药物的敏感性更高。
（3）肾脏再生
在体外培养人多能干细胞，可诱导其分化为肾集合管类器官，并且集合管上皮具有电生理功能。
（4）肾脏异种再生
通过胚胎互补诱导多能干细胞，可在猪体内产生人源化中肾。未来，有希望在新生的猪体内“培育”出具有生理功能的人源肾脏，这将为解决器官移植供体短缺的难题提供极具吸引力的替代方案。
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