Dekel Benjamin, Zangi Lior, Shezen Elias, Reich-Zeliger Shlomit, Eventov-Friedman Smadar, Katchman Helena, Jacob-Hirsch Jasmin, Amariglio Ninette, Rechavi Gideon, Margalit Raanan, Reisner Yair
Weizmann Institute of Science, Department of Immunology, Rehovot, Israel.
J Am Soc Nephrol. 2006 Dec;17(12):3300-14. doi: 10.1681/ASN.2005020195. Epub 2006 Nov 8.
Tissue engineering and cell therapy approaches aim to take advantage of the repopulating ability and plasticity of multipotent stem cells to regenerate lost or diseased tissue. Recently, stage-specific embryonic kidney progenitor tissue was used to regenerate nephrons. Through fluorescence-activated cell sorting, microarray analysis, in vitro differentiation assays, mixed lymphocyte reaction, and a model of ischemic kidney injury, this study sought to identify and characterize multipotent organ stem/progenitor cells in the adult kidney. Herein is reported the existence of nontubular cells that express stem cell antigen-1 (Sca-1). This population of small cells includes a CD45-negative fraction that lacks hematopoietic stem cell and lineage markers and resides in the renal interstitial space. In addition, these cells are enriched for beta1-integrin, are cytokeratin negative, and show minimal expression of surface markers that typically are found on bone marrow-derived mesenchymal stem cells. Global gene profiling reveals enrichment for many genes downstream of developmental signaling molecules and self-renewal pathways, such as TGF-beta/bone morphogenic protein, Wnt, or fibroblast growth factor, as well as for those that are involved in specification of mesodermal lineages (myocyte enhancer factor 2A, YY1-associated factor 2, and filamin-beta). In vitro, they are plastic adherent and slowly proliferating and result in inhibition of alloreactive CD8(+) T cells, indicative of an immune-privileged behavior. Furthermore, clonal-derived lines can be differentiated into myogenic, osteogenic, adipogenic, and neural lineages. Finally, when injected directly into the renal parenchyma, shortly after ischemic/reperfusion injury, renal Sca-1(+)Lin(-) cells, derived from ROSA26 reporter mice, adopt a tubular phenotype and potentially could contribute to kidney repair. These data define a unique phenotype for adult kidney-derived cells, which have potential as stem cells and may contribute to the regeneration of injured kidneys.
组织工程和细胞治疗方法旨在利用多能干细胞的再填充能力和可塑性来再生受损或患病组织。最近，特定阶段的胚胎肾祖组织被用于再生肾单位。通过荧光激活细胞分选、微阵列分析、体外分化测定、混合淋巴细胞反应以及缺血性肾损伤模型，本研究试图识别和表征成年肾脏中的多能器官干/祖细胞。本文报道了表达干细胞抗原-1（Sca-1）的非肾小管细胞的存在。这群小细胞包括一个CD45阴性部分，其缺乏造血干细胞和谱系标记物，位于肾间质空间。此外，这些细胞富含β1整合素，细胞角蛋白阴性，并且表面标记物的表达极低，这些标记物通常在骨髓来源的间充质干细胞上发现。全基因组分析显示，许多发育信号分子和自我更新途径下游的基因富集，如转化生长因子-β/骨形态发生蛋白、Wnt或成纤维细胞生长因子，以及那些参与中胚层谱系特化的基因（肌细胞增强因子2A、YY1相关因子2和细丝蛋白-β）。在体外，它们具有可塑性贴壁且增殖缓慢，并导致同种异体反应性CD8(+) T细胞受到抑制，这表明其具有免疫特权行为。此外，克隆衍生系可分化为肌源性、成骨细胞、脂肪生成和神经谱系。最后，当在缺血/再灌注损伤后不久直接注射到肾实质中时，源自ROSA26报告小鼠的肾Sca-1(+)Lin(-)细胞会呈现肾小管表型，并可能有助于肾脏修复。这些数据定义了成年肾脏来源细胞的独特表型，它们具有作为干细胞的潜力，并可能有助于受损肾脏的再生。
