Progress toward the Clinical Application of Mesenchymal Stromal Cells and Other Disease-Modulating Regenerative Therapies: Examples from the Field of Nephrology.
Progress toward the Clinical Application of Mesenchymal Stromal Cells and Other Disease-Modulating Regenerative Therapies: Examples from the Field of Nephrology.
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DOI：
10.34067/kid.0005692020
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发表时间：
2021-03
期刊：
影响因子：
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通讯作者：
Griffin MD
中科院分区：
文献类型：
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作者：
Hickson LJ;Herrmann SM;McNicholas BA;Griffin MD
再生医学借鉴了干细胞生物学、胚胎发育、伤口愈合和衰老的基本知识，试图通过积极修复患病组织或产生新的器官和组织来开发补充或取代传统治疗方法的治疗策略。在再生医学领域内的各种临床-翻译策略中，有几种可以广泛地描述为通过与患者细胞的局部或系统相互作用间接促进疾病的解决，而不是永久整合或直接形成新的原始组织。在这篇综述中，我们将重点放在这些我们称之为疾病调节再生疗法(DMRT)的疗法上，以及它们在四个不同的肾脏病领域的临床应用程度：肾血管病(RVD)、脓毒症相关性AKI(SA-AKI)、糖尿病肾病(DKD)和肾移植(KTX)。正如我们所描述的，在这些适应症的人类临床试验中，DMRT进展最快的是间充质干细胞/基质细胞(MSCs)，它通过不同的旁分泌机制有效地调节缺血、炎症、纤维化和免疫介导的组织损伤。在KTX，几项早期临床试验也测试了体外扩大调节性免疫细胞疗法的可能性，以促进供者特异性耐受，防止或解决同种异体移植损伤。其他有希望的DMRT，包括成体干细胞/祖细胞、干细胞来源的细胞外小泡和可植入水凝胶/生物材料，仍处于这些肾脏疾病的不同临床前转换阶段。到目前为止(2021年)，还没有DMRT获得市场批准用于RVD、SA-AKI、DKD或KTX患者，需要临床试验证明最终的、成本效益高的患者受益。尽管如此，在了解MSCs和其他DMRT特定疾病的作用机制方面取得了令人兴奋的进展，再加上对肾组织损伤的病理生理学基础的了解不断增加，以及从开创性的早期临床试验中获得的经验提供了乐观的看法，即针对各种肾脏疾病的有影响力的再生治疗将在未来几年出现。
Drawing from basic knowledge of stem-cell biology, embryonic development, wound healing, and aging, regenerative medicine seeks to develop therapeutic strategies that complement or replace conventional treatments by actively repairing diseased tissue or generating new organs and tissues. Among the various clinical-translational strategies within the field of regenerative medicine, several can be broadly described as promoting disease resolution indirectly through local or systemic interactions with a patient’s cells, without permanently integrating or directly forming new primary tissue. In this review, we focus on such therapies, which we term disease-modulating regenerative therapies (DMRT), and on the extent to which they have been translated into the clinical arena in four distinct areas of nephrology: renovascular disease (RVD), sepsis-associated AKI (SA-AKI), diabetic kidney disease (DKD), and kidney transplantation (KTx). As we describe, the DMRT that has most consistently progressed to human clinical trials for these indications is mesenchymal stem/stromal cells (MSCs), which potently modulate ischemic, inflammatory, profibrotic, and immune-mediated tissue injury through diverse paracrine mechanisms. In KTx, several early-phase clinical trials have also tested the potential for ex vivo–expanded regulatory immune cell therapies to promote donor-specific tolerance and prevent or resolve allograft injury. Other promising DMRT, including adult stem/progenitor cells, stem cell–derived extracellular vesicles, and implantable hydrogels/biomaterials remain at varying preclinical stages of translation for these renal conditions. To date (2021), no DMRT has gained market approval for use in patients with RVD, SA-AKI, DKD, or KTx, and clinical trials demonstrating definitive, cost-effective patient benefits are needed. Nonetheless, exciting progress in understanding the disease-specific mechanisms of action of MSCs and other DMRT, coupled with increasing knowledge of the pathophysiologic basis for renal-tissue injury and the experience gained from pioneering early-phase clinical trials provide optimism that influential, regenerative treatments for diverse kidney diseases will emerge in the years ahead.