Cell Sheet Tissue Engineering Center (CSTEC), University of Utah, Salt Lake City, Utah, USA.
Department of Molecular Pharmaceutics, University of Utah, Salt Lake City, Utah, USA.
Tissue Eng Part C Methods. 2023 Feb;29(2):54-62. doi: 10.1089/ten.TEC.2022.0200.
Chronic kidney disease (CKD) is the irreversible loss of nephron function, leading to a build-up of toxins, prolonged inflammation, and ultimately fibrosis. Currently, no effective therapies exist to treat CKD due to its complex pathophysiology. Mesenchymal stem/stromal cell (MSC) transplantation is a promising strategy to treat kidney diseases, and multiple clinical trials are currently ongoing. We previously demonstrated that rat bone marrow-derived MSC (BMSC) sheets transplanted onto surgically decapsulated kidney exert therapeutic effects that suppressed renal fibrosis progression based on enhanced vascularization. However, there are clinical concerns about kidney decapsulation such as impaired glomerular filtration rate and Na ion and HO excretion, leading to kidney dysfunction. Therefore, for transitioning from basic research to translational research using cell sheet therapy for kidney disease, it is essential to develop a new cell sheet transplantation strategy without kidney decapsulation. Significantly, we employed cell sheets engineered from clinical-grade human clonal BMSC (cBMSC) and transplanted these onto intact renal capsule to evaluate their therapeutic ability in the rat ischemia-reperfusion injury (IRI) model. Histological analysis 1-day postsurgery showed that cBMSC sheets engrafted well onto intact renal capsule. Interestingly, some grafted cBMSCs migrated into the renal parenchyma. At 1-3 days postsurgery (acute stage), grafted cBMSC sheets prevented tubular epithelial cell injury. At 28 days postsurgery (chronic phase), we observed that grafted cBMSC sheets suppressed renal fibrosis in the rat IRI model. Taken together, engineered cBMSC sheet transplantation onto intact renal capsule suppresses tubular epithelial cell injury and renal fibrosis, supporting further development as a possible clinically relevant strategy. Impact statement Chronic kidney disease (CKD) produces irreversible loss of nephron function, leading to toxemia, prolonged inflammation, and ultimately kidney fibrosis. Currently, no therapies exist to effectively treat CKD due to its complex pathophysiology. Mesenchymal stem/stromal cells (MSCs) are widely known to secret therapeutic paracrine factors, which is expected to provide a new effective therapy for unmet medical needs. However, unsatisfied MSC quality and administration methods to patients limit their therapeutic effects. In this study, we engineered clonal bone marrow-derived MSC sheets and established clinically relevant cell sheet transplantation strategy to treat renal fibrosis, which would improve MSC treatment for kidney disease.
慢性肾脏病（CKD）是指肾单位功能的不可逆丧失，导致毒素积聚、炎症持续时间延长，最终导致纤维化。目前，由于其复杂的病理生理学，尚无有效的治疗方法。间充质干细胞/基质细胞（MSC）移植是治疗肾脏疾病的一种有前途的策略，目前正在进行多项临床试验。我们之前的研究表明，移植到手术去被膜肾脏上的大鼠骨髓源性 MSC（BMSC）片基于增强的血管生成而发挥抑制肾纤维化进展的治疗作用。然而，去被膜肾脏存在临床问题，如肾小球滤过率和钠离子及水排泄受损，导致肾功能障碍。因此，为了将细胞片疗法从基础研究转化为肾脏疾病的转化研究，开发一种新的无需去被膜的细胞片移植策略是至关重要的。重要的是，我们采用了临床级别的人克隆 BMSC（cBMSC）工程化的细胞片，并将其移植到完整的肾被膜上，以评估它们在大鼠缺血再灌注损伤（IRI）模型中的治疗能力。手术后 1 天的组织学分析表明，cBMSC 片很好地移植到完整的肾被膜上。有趣的是，一些移植的 cBMSCs 迁移到肾实质中。手术后 1-3 天（急性期），移植的 cBMSC 片可防止肾小管上皮细胞损伤。手术后 28 天（慢性期），我们观察到移植的 cBMSC 片可抑制大鼠 IRI 模型中的肾纤维化。总之，工程化的 cBMSC 片移植到完整的肾被膜上可抑制肾小管上皮细胞损伤和肾纤维化，支持其作为一种潜在的临床相关策略进一步发展。
