在臺灣末期腎病變接受長期透析病人的發生率及盛行率一直高居世界前兩名。然而目前對於慢性尿毒症的治療只有血液透析、腹膜透析以及腎臟移植。受限於器官之短缺，大多數病人只能靠長期透析維持生命。找尋讓受傷的腎臟恢復功能甚至再生腎臟一直是迫切解決的課題。隨著其他器官幹細胞的發現以及對幹細胞特性，包括幫助受損器官修補之潛能的了解，運用幹細胞於治療腎衰竭是一新的策略。有別於單一藥物的治療，幹細胞可於受傷組織分泌細胞激素、改善血管功能或直接分化為需要的細胞來幫忙腎臟再生。在囓齒動物骨髓間質幹細胞可以藉由旁泌素作用改善腎衰竭，而腎臟幹細胞在腎衰竭再生過程中所扮演的角色仍不清楚。
急性腎小管壞死是臨床上最典型的急性腎衰竭模式。在觀察急性腎小管壞死後的再生過程中，藉由組織染色之分析發現正常腎臟組織中腎小管上皮細胞不會表現vimentin，只有間質細胞會表現vimentin。在急性腎臟傷害12小時後，圍繞在受損的腎小管上皮細胞周圍的間質細胞有明顯增生現象且都表現vimentin。第2~4天隨著腎小管上皮細胞的再生，除了間質vimentin陽性細胞增生外，再生扁平的腎小管上皮也同時出現vimentin染色陽性細胞。之後當腎小管上皮細胞完成修補後便不再表現vimentin。由此推論在急性腎衰竭後，腎臟間質細胞可能直接參與腎小管上皮細胞的再生。進一步檢視已知間質細胞的標記發現在急性腎臟傷害1天內只有少數細胞是纖維細胞或血管內皮細胞，多數仍是未知的細胞。臆測腎臟幹細胞可能就在這些細胞中。
另外，在急性腎臟傷害之前給予一次BrdU注射以作為追蹤間質細胞的標記。經過急性腎臟衰竭後藉由組織染色發現﹕第12小時85% BrdU染色陽性細胞存在腎臟間質。隨著腎小管上皮細胞的再生，第2~4天BrdU染色陽性細胞也跟著出現在腎小管中，到第4天高達75% BrdU染色陽性細胞出現在腎小管。進一步由ELISA檢測腎臟組織證實經過一次BrdU注射後腎臟BrdU含量在1天達巔峰，之後含量漸減至3天達定值，並穩定持續到7天。由此動物實驗模式證明急性腎衰竭後，腎臟BrdU存留細胞可能由間質移到腎小管，推論腎臟間質細胞可能直接參與腎小管上皮細胞的再生。
我們使用Myh9螢光轉殖鼠，經由適當的過濾篩選、螢光細胞的煉選以及持續的細胞繼代培養，成功得到發螢光的腎臟幹細胞。其基因表現有別於骨髓間質幹細胞，且這些細胞具有下列特性:經過數十代的培養仍無老化現象，表現幹細胞及腎臟幹細胞的標記如Oct4、Nanog、Pax2、Wnt-4、WT-1，但並不表現CD34、Sca-1、CD45、E-cadherin、vWF等細胞標記以及可分化為血管內皮細胞、成骨細胞及腎小管上皮細胞。藉由Oct4及綠螢光的雙免疫組織染色確認腎臟幹細胞分離自腎髓質及乳突之間質部。在急性缺血性腎衰竭後，藉著注射腎臟幹細胞到腎臟內，可以降低血中尖峰尿素氮值，栓塞區域以及壞死傷害。受傷七天後，腎臟幹細胞可形成血管及腎小管上皮細胞。此外注射腎臟幹細胞治療也可以減少急性缺血性腎衰竭造成的死亡率。本研究顯示我們驗證了成鼠腎臟間質中存在腎臟幹細胞，且在急性腎衰竭中，腎臟幹細胞有助於腎臟的修補並可延長老鼠的存活。運用腎臟幹細胞我們不僅開啟治療腎臟衰竭之另一扇窗，以此研究為基石我們將可進一步探討並了解腎臟幹細胞在急性腎衰竭再生過程中所扮演的角色及功能並進一步闡明幹細胞參與組織再生之機轉。

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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