Stem cell marker TRA-1-60 is expressed in foetal and adult kidney and upregulated in tubulo-interstitial disease.
ABSTRACT The kidney has an intrinsic ability to repair itself when injured. Epithelial cells of distal tubules may participate in regeneration. Stem cell marker, TRA-1-60 is linked to pluripotency in human embryonic stem cells and is lost upon differentiation. TRA-1-60 expression was mapped and quantified in serial sections of human foetal, adult and diseased kidneys. In 8- to 10-week human foetal kidney, the epitope was abundantly expressed on ureteric bud and structures derived therefrom including collecting duct epithelium. In adult kidney inner medulla/papilla, comparisons with reactivity to epithelial membrane antigen, aquaporin-2 and Tamm-Horsfall protein, confirmed extensive expression of TRA-1-60 in cells lining collecting ducts and thin limb of the loop of Henle, which may be significant since the papillae were proposed to harbour slow cycling cells involved in kidney homeostasis and repair. In the outer medulla and cortex there was rare, sporadic expression in tubular cells of the collecting ducts and nephron, with positive cells confined to the thin limb and thick ascending limb and distal convoluted tubules. Remarkably, in cortex displaying tubulo-interstitial injury, there was a dramatic increase in number of TRA-1-60 expressing individual cells and in small groups of cells in distal tubules. Dual staining showed that TRA-1-60 positive cells co-expressed Pax-2 and Ki-67, markers of tubular regeneration. Given the localization in foetal kidney and the distribution patterns in adults, it is tempting to speculate that TRA-1-60 may identify a population of cells contributing to repair of distal tubules in adult kidney.
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ABSTRACT: Kidney disease has reached epidemic proportions and is associated with high mortality and morbidity rates. Stem cell-based therapy may effectively treat kidney damage by cell transplantation. The breakthrough discovery using a combination of four transcription factors to reprogram genetically somatic cells into induced pluripotent stem (iPS) cells was a milestone in stem cell therapy. The lentivirus was packaged containing OCT4, SOX2, c-MYC and KLF4 transcription factors and then transfected mouse renal tubular epithelial cells (RTECs). The colonies were picked up at 21 days and were tested by cytochemistry, immunofluorescence assay and quantitative real-time polymerase chain reaction. Viral transgene expression levels were also assessed by quantitative analysis. Additionally, embryoid bodies from iPS cells were formed, and immunofluorescence and teratoma assays were performed. Karyotype analysis of mouse RTEC-derived iPS cells was also performed. The iPS cells were indistinguishable from mouse embryonic stem cells with respect to colony morphology, the expression of pluripotency-associated transcription factors and surface markers, embryoid body-mediated differentiation potential and teratoma assays. Quantitative polymerase chain reaction demonstrated that the lentiviral transgenes were largely silenced. The mouse RTEC-derived iPS cells exhibited a normal karyotype of 40,XY. iPS cells can be produced using mouse RTECs, which would be helpful in investigations to ameliorate the symptoms of kidney disease and to slow the progression of kidney disease by in vitro and in vivo animal studies.Cytotherapy 02/2013; · 3.06 Impact Factor
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ABSTRACT: Several hypotheses have been developed to interpret the progression of tubulointerstitial fibrosis (TF), including senescence, epithelial-mesenchymal transition, inflammation, chronic hypoxia, and reactive oxygen species. All of these hypotheses are based on persistent cell injury and localized cell death. Proliferation of neighboring renal tubular epithelial cells (RTECs) is beneficial for organ function recovery from acute injury. However, compensatory proliferation is not always advantageous, as the proliferating cells are vulnerable to ongoing detrimental stimuli, such as inflammation, endocrine stress, high blood pressure, hypoxia/ischemia, and the like. Cell injury and death promotes secretion of growth factors, which evokes proliferation of RTECs; entering the cell cycle makes the RTECs more vulnerable to injury and death. Under persistent stress, death and proliferation are mutually promoted and form the vicious circle that triggers, maintains, and augments the inflammation and progression of TF. We hypothesize that the "proliferation-death" circle is another important pathophysiologic mechanism of TF onset. Through this hypothesis, this paper interprets the development and progression of TF. Moreover, the vicious circle may be universal, underlying the development of inflammation and fibrosis in various organs and tissues. The hypothesis also suggests a potential therapy strategy for the inhibition of fibrosis.Medical Hypotheses 01/2014; · 1.18 Impact Factor
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ABSTRACT: Epithelial-mesenchymal transition (EMT) of tubular epithelial cells (TECs) is commonly considered as the major mechanism leading to renal fibrosis in chronic kidney diseases (CKD) injury. We raise the hypothesis that EMT in adult kidney may be an event of "atavistic" phenotypic transition, which mimics but reverses the genetic and cellular processes of development of renal tubules. Transformed TECs may be regarded as induced mesenchymal stem-like cells, representing a cellular self-adaptation when in acute or chronic injury. The reasons are as follows: (1) Embryonic gene WT1 and Pax2, which govern tubule development, have been found to re-express during tubular EMT when facing injury. (2) The common factors that induce EMT in vitro, like IL-1, angiotension II and hypoxia could also promote WT1 and/or Pax2 re-expression. (3) Expression of WT1 and Pax2 are found to be associated with progenitor cells. (4) Beside embryonic gene WT1 and Pax2, we also found that some stem cell markers like CD133 were expressed during EMT process. (5) The process of EMT is not only take place in chronic kidney injury (CKD), but also in acute kidney injury (AKI) as well. (6) The phenotype transition of TECs and genetic event during AKI are entirely consistent with what happened in CKD, but the outcome is completely different. Thus, we thought tubular injury of CKD and AKI may share a common initiative repair mechanism: tubular EMT, that is TECs are transformed into induced mesenchymal stem-like cells, and then interpret the injurious signal differently in acute versus chronic conditions, so as to possess a divergent fates, tubular regeneration or fibrosis formation, depending on a different microenvironment or the duration of the injury. In this sense, tubular EMT could be purposefully orientated into a constructively pathway that repair kidney injury via tubular regeneration, matrix remodeling and tissue structure and function restoration.Medical Hypotheses 04/2013; · 1.18 Impact Factor