| Summary: | 博士 === 國立成功大學 === 臨床醫學研究所 === 98 === In Taiwan, the incidence of end-stage renal disease ranked first and the prevalence ranked second in the world. Patients with end-stage renal disease need hemodialysis, peritoneal dialysis or kidney transplant to maintain their life. For the shortage of available organ, most of the patients are under regular dialysis. To accelerate renal repair or even make a functioning kidney is the emergent issue to be solved and interesting topic for research. Following the discovery of tissue-specific progenitor cells in other organs and their ability to improve regeneration after injury, progenitor cell-based therapy is a new strategy in the treatment of acute kidney injury and has potentially more value than single-agent drug therapy due to the highly versatile response of cells to their environment. These cells may not only secrete cytokines within the injured kidney, but also participate in tubular cell proliferation or angiogenesis to facilitate renal regeneration. In rodents, increasing evidence suggests that the therapeutic potential of mesenchymal stem cells derived from bone marrow could be beneficial in the kidney injury. Thereby, we hypothesize that kidney progenitor cells may accelerate renal regeneration after injury.
We first observed the regenerative process of acute tubular necrosis in rodents. In the normal kidney, only interstitial cells but not tubular cells expressed vimentin. Following acute renal failure, vimentin-positive renal interstitial cells proliferated and surrounded the damaged renal tubules as early as 12 hours after injury. Within the regenerating tubules, vimentin staining was found intensely two days after injury, and disappeared after full recovery of tubular epithelial cells. By known interstitial cell markers, only few vimentin-positive renal interstitial cells were characterized as endothelial cells or fibroblasts one day after acute renal failure. Most of the other proliferating cells were not specified and we hypothesize that kidney progenitor cells could reside in these areas.
Using bromodeoxyuridine (BrdU) as a marker of proliferating cells, we monitor the distribution of the interstitial cells by immunohistochemistry during acute renal failure. Following one injection of BrdU, eighty five percent of BrdU labeling cells located in the interstitium 12 hours after acute renal failure and the count decreased to 25% at the 4th day. Interestingly, BrdU labeling cells redistributed to the regenerating tubules at the 1st and 4th day. Seventy-five percentage of BrdU labeling cells located in the tubules at the 4th day. As assessed by ELISA, the uptake of BrdU in the kidney peaked at the 1st day, decreased to constant level after 3 days, and maintained till 7 days following one injection of BrdU before acute renal failure. These results indicate that interstitial cells might be engaged in the process of tubular regeneration after acute renal failure.
We test the hypothesis that renal progenitor cells isolated from adult mouse kidney accelerate renal regeneration via participation in the repair process. A unique population of cells exhibiting characteristics consistent with renal progenitor cells, mouse kidney progenitor cells (MKPC), was isolated from Myh9 targeted mutant mice. Features of these cells include: (1) spindle-shaped morphology, (2) self-renewal of more than 100 passages without evidence of senescence, (3) expression of Oct-4, Pax-2, Wnt-4, WT-1, vimentin, alpha-smooth muscle actin, CD29 and S100A4 but no SSEA-1, c-kit, or other markers of more differentiated cells. MKPC exhibit plasticity as demonstrated by the ability to differentiate into endothelial cells and osteoblasts in vitro and endothelial cells and tubular epithelial cells in vivo. The origin of the isolated MKPC was from the interstitium of medulla and papilla. Importantly, intra-renal injection of MKPC in mice with ischemic injury rescued renal damage, as manifested by decreases in peak serum urea nitrogen, the infarct zone and the necrotic injury. Seven days after the injury, some MKPC formed vessels with red blood cells inside and some incorporated into renal tubules. In addition, MKPC treatment reduces the mortality in mice after ischemic injury. Our results indicate that MKPC represent a multipotent adult progenitor cell population, which may contribute to the renal repair and prolong survival after ischemic injury. The PhD study not only raised a novel method to treat acute renal failure but also open a new window to elucidate the relationship between kidney progenitor cells and tubular regeneration. Based on these, we will be able to unveil the mechanism of how tissue-specific progenitor cells involve in the process of tissue regeneration.
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