We investigated the proliferative capacity of renal proximal tubular cells in healthy rats. Previously, we observed that tubular cells originate from differentiated cells. We now found 1) by application of bromo-deoxyuridine (BrdU) for 14 days and costaining for BrdU, and the G 1-phase marker cyclin D1 that the bulk of cells in the S3 segment of juvenile rats were involved in proliferation; 2) that although the proliferation rate was about 10-fold higher in juvenile rats compared with adult rats, roughly 40% of S3 cells were in G 1 in both groups; 3) that after a strong mitotic stimulus (lead acetate), proliferation was similar in juveniles and adults; 4) that there was a high incidence of cyclin D1-positive cells also in the healthy human kidney; and 5) by labeling dividing cells with BrdU for 2 days before the application of lead acetate and subsequent costaining for BrdU and cell cycle markers, that, although a strong mitotic stimulus does not abolish the period of quiescence following division, it shortens it markedly. Thus the capacity of the proximal tubule to rapidly recruit cells into division relies on a large reserve pool of cells in G 1 and on the shortening of the obligatory period of quiescence that follows division. kidney; cyclin D1; bromodeoxyuridine; stem cells; regeneration HOW THE KIDNEY maintains the homeostasis of tubular epithelial cell number has been a fundamental question for years. Since differentiated cells in most tissues, including renal tubules, have only a limited life span, it is crucial for these cells to be replaced to maintain organ function. Also a variation in tissue mass as seen during physiological adaptation encompasses the production of specialized cells. Furthermore, after injury, the generation of new cells is a prerequisite to restore the normal function of the injured organ.The source of newly formed renal epithelial cells is debated. Some studies show that novel cells are derived from divisions of differentiated cells (1,10,27), and others claim that a subpopulation in the renal tubular epithelial cells function as progenitor cells (5,9,16,19). In addition, hematopoietic stem cells (12,15,21,22) and mesenchymal stem cells (18) have been shown to be able to repopulate the renal tubular system; however, under physiological conditions tubular cells originating from extrarenal stem cells are not detectable in the kidney, and even after severe organ injury these cells constitute only a small population (7).Our previous studies revealed that tubular cell proliferation in healthy rats rely on the division of differentiated cells (25). Furthermore, we were unable to detect any slow-cycling stem cells or rapidly cycling transit amplifying (TA) cells to support a "classic" stem cell system (26).In the present study we address the question whether the capacity to divide is restricted to a small subpopulation of the differentiated cells in S3 or whether it is broadly distributed among the cells in that segment. To that aim we investigated the cycling behavior of tubular cells in...
In this study we demonstrate that different histopathological types of follicular thyroid carcinomas have distinct miRNA expression profiles. MiR-885-5p is highly up-regulated in oncocytic follicular carcinomas and may serve as a diagnostic marker for these tumors. A small set of deregulated miRNAs allows for an accurate discrimination between follicular carcinomas and hyperplastic nodules and can be used diagnostically in fine-needle aspiration biopsies.
Tubulo-interstitial Wbrosis is a constant feature of chronic renal failure and it is suspected to contribute importantly to the deterioration of renal function. In the Wbrotic kidney there exists, besides normal Wbroblasts, a large population of myoWbroblasts, which are supposedly responsible for the increased production of intercellular matrix. It has been proposed that myoWbroblasts in chronic renal failure originate from the transformation of tubular cells via epithelial-mesenchymal transition (EMT) or from inWltration by bone marrow-derived precursors. Little attention has been paid to the possibility of a transformation of resident Wbroblasts into myoWbroblasts in renal Wbrosis. Therefore we examined the fate of resident Wbroblasts in the initial phase of renal Wbrosis in the classical model of unilateral ureter obstruction (UUO) in the rat. Rats were perfusion-Wxed on days 1, 2, 3 and 4 after ligature of the right ureter. Starting from 1 day of UUO an increasing expression of alpha-smooth muscle actin ( SMA) in resident Wbroblasts was revealed by immunoXuorescence and conWrmed by the observation of bundles of microWlaments and webs of intermediate Wlaments in the electron microscope. Inversely, there was a decreased expression of 5Ј-nucleotidase (5ЈNT), a marker of renal cortical Wbroblasts. The RER became more voluminous, suggesting an increased synthesis of matrix. Intercellular junctions, a characteristic feature of myoWbroblasts, became more frequent. The mitotic activity in Wbroblasts was strongly increased. Renal tubules underwent severe regressive changes but the cells retained their epithelial characteristics and there was no sign of EMT. In conclusion, after ureter ligature, resident peritubular Wbroblasts proliferated and they showed progressive alterations, suggesting a transformation in myoWbroblasts. Thus the resident Wbroblasts likely play a central role in Wbrosis in that model.
We searched for evidence for a contribution of stem cells in growth of the proximal S3 segments of healthy rats. According to the stem cell model, stem cells are undifferentiated and slow cycling; the bulk of cycling cells are transit amplifying, rapidly cycling cells. We show the following. 1) By continuous application of a thymidine analog (ThA) for 7 days, S3 proximal epithelial cells in healthy kidneys display a high-cycling rate. 2) Slow-cycling cells, identified by lack of ThA uptake during 14 days of continuous ThA application up to death and by expression of the cell cycle protein Ki67 at death, have the same degree of differentiation as quiescent cells. 3) To detect rapidly cycling cells, rats were killed at various time points after injection of a ThA. Double immunofluorescence for ThA and a cell cycle marker was performed, with colocalization indicating successive divisions. During one week after division, daughter cells display a very low proliferation rate, indicating the absence of rapidly cycling cells. 4) Labeling with cyclin D1 showed that this low proliferation rate is due to cycle arrest. 5) More than 50% of the S3 cells entered the cell cycle 36 h after a potent proliferative stimulus (lead acetate injection). We conclude that generation of new cells in the proximal tubule relies on division of differentiated, normally slow-cycling cells. These may rapidly enter the cycle under an adequate stimulus.
To determine whether metastasis to brain is associated with altered expression patterns of integrins, we investigated the expression of avb3, avb5, avb6 and avb8 integrins in primary malignancies and metastases to brain of breast, lung and renal carcinomas and in malignant melanoma. Inhibitors of av integrins are currently in clinical trials for glioblastoma. The role of integrins in the process of brain metastasis from other human tumors is unknown. Immunohistochemistry with novel integrin subtype specific rabbit monoclonal antibodies was performed on tissue microarrays of archival material of surgical biopsies taken from primary tumors and brain metastases. Integrin avb3 expression was increased in brain metastases compared to primary tumors of breast adenocarcinoma, non-small cell lung cancer, renal clear cell cancer and malignant cutaneous melanoma (all p < 0.01). Similarly, integrin avb8 expression was increased in brain metastases compared to primary tumors of breast cancer (p < 0.0001), lung cancer (p < 0.01) and renal cancer (p < 0.0001), with a similar trend in metastatic melanoma. Integrin avb5 was expressed in most primary tumors (98% breast cancer; 67% lung cancer; 90% renal cancer; 89% melanoma) and showed a stronger expression in brain metastases compared to primary tumors from lung cancer and melanoma (p < 0.05). Also integrin avb6 expression was increased in brain metastases compared to primary breast cancer (p < 0.001). Conclusions: The stronger av-integrin expression in brain metastases, especially of avb3 and avb8 integrins, suggests that certain av integrin are involved in the process of brain metastasis. av Integrins may be therapeutic targets for patients with metastatic cancer in brain.Some 45% of cancer patients develop brain metastases during the course of their illness, with 98,000 to 170,000 new cases diagnosed each year in the U.S. alone. 1 There is an increasing prevalence of brain metastases, as primary treatments have become more effective, and people with cancer live longer after initial treatment. Changes in cellular protein levels accompany the metastatic processes, but the molecular details and drivers of the process are unknown for most cancers. These changes allow tumor cells to escape the primary, and to attach and survive at foreign sites, 2,3 which strongly implicates a role for an altered activity of integrins during tumor progression. Integrins are a family of heterodimeric transmembrane glycoproteins that classically bind the extracellular matrix (ECM) to influence cell attachment, motility, cell proliferation, invasion and tumor cell metastasis. 4,5 Several integrin-dependent mechanisms may influence metastasis. Integrins influence tumor cell survival 6 and migration and invasive processes, 7 thereby affecting tumor growth and metastasis. 8 Different integrins in different cellular contexts can either enhance survival or initiate apoptosis. 6,9,10 Although integrins cannot transform cells, several cooperate with oncogenes or receptor tyrosine kinases 6 to influence tum...
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