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Benidipine Protects Kidney through Inhibiting ROCK1 Activity and Reducing the Epithelium-Mesenchymal Transdifferentiation in Type 1 Diabetic Rats  [PDF]
Ganlin Wu,Meirong Xu,Kui Xu,Yilan Hu
Journal of Diabetes Research , 2013, DOI: 10.1155/2013/174526
Abstract: We investigated the protective effect of benidipine, by testing the changes of the activity of Rho kinase and transdifferentiation of renal tubular epithelium cells in vivo. Wistar rats were randomly divided into two groups: normal (N) and diabetes. STZ were used to make the rats type 1 diabetic and were randomly assigned as diabetes without treatment (D), diabetes treated with benidipine (B), and diabetes treated with fasudil (F) and treated for 3 months. Immunohistochemistry and western blotting were for protein expressions of ROCK1, -SMA, and E-cadherin and real-time PCR for the mRNA quantification of ROCK1. Compared with N group, D group had significant proliferation of glomerular mesangial matrix, increased cell number, thickened basement membrane, widely infiltrated by inflammatory cells and fibrosis in the renal interstitial, and dilated tubular. Those presentations in F and B groups were milder. Compared with N group, D group showed elevated MYPT1 phosphorylation, increased expression of ROCK1, -SMA protein, and ROCK1 mRNA and decreased expression of E-cadherin protein. B group showed attenuated MYPT1 phosphorylation, decreased ROCK1, -SMA protein, and ROCK1 mRNA expression and increased expression of E-cadherin protein. In conclusion, benidipine reduces the epithelium-mesenchymal transdifferentiation and renal interstitial fibrosis in diabetic kidney by inhibiting ROCK1 activity. 1. Introduction Benidipine is a triple calcium channel blocker, simultaneously blocking L, T, and N type channels. It is reported that the effect on T channel is stronger than that on L channel [1], making it a great potential protection for kidney. A number of studies explored the Rho signaling pathway, renal interstitial fibrosis, and tubular epithelium cell transdifferentiation (EMT) [2–4]. The blocking of T calcium channel (TCC) was reported to inhibit the activity of Rho kinase [5], and this is essential in podocyte effacement in immune complex-mediated glomerular disease and other kidney injuries [6]. Furthermore, under cellular stress, Rho kinase activation results in cytoskeletal rearrangement, stress fiber formation, and loss of cellular integrity and function [7]. Rho kinase inhibition prevented these changes and enhanced process formation [8]. These suggested that blocking T channel may have a protective effect on diabetic kidney and reduce epithelium-mesenchymal transdifferentiation and fibrosis via inhibiting ROCK1 (Rho kinase 1) activity. It was suggested that fasudil, a Rho kinase inhibitor, may attenuate EMT through reduced activation of RhoA/ROCK
Evidence for Bone Marrow Adult Stem Cell Plasticity: Properties, Molecular Mechanisms, Negative Aspects, and Clinical Applications of Hematopoietic and Mesenchymal Stem Cells Transdifferentiation  [PDF]
Ivana Catacchio,Simona Berardi,Antonia Reale,Annunziata De Luisi,Vito Racanelli,Angelo Vacca,Roberto Ria
Stem Cells International , 2013, DOI: 10.1155/2013/589139
Abstract: In contrast to the pluripotent embryonic stem cells (ESCs) which are able to give rise to all cell types of the body, mammalian adult stem cells (ASCs) appeared to be more limited in their differentiation potential and to be committed to their tissue of origin. Recently, surprising new findings have contradicted central dogmas of commitment of ASCs by showing their plasticity to differentiate across tissue lineage boundaries, irrespective of classical germ layer designations. The present paper supports the plasticity of the bone marrow stem cells (BMSCs), bringing the most striking and the latest evidences of the transdifferentiation properties of the bone marrow hematopoietic and mesenchymal stem cells (BMHSCs, and BMMSCs), the two BM populations of ASCs better characterized. In addition, we report the possible mechanisms that may explain these events, outlining the clinical importance of these phenomena and the relative problems. 1. Introduction 1.1. Evidence for BMSCs Plasticity It has long been believed that the differentiation potential of ASCs is restricted to the production of the cell types normally found in the organ in which ASCs reside. Classical experiments showed that when fragments or cells dissociated from an organ or a tissue are transplanted to a new site or cultured, they tend to maintain their originalcharacter; although they may lose some of their properties, they usually do not acquire characteristics of a different cell lineage [1]. The first suggestion that ASCs, committed to a specific developmental lineage, switch into another cell type of an unrelated tissue (transdifferentiation) came from studies of whole BM transplantation in humans and animal models. In 1997 Eglitis and Mezey reported that transplanted mouse BM cells could give rise to brain astrocytes in adult mice [2]. The most striking suggestion of stem cell plasticity was published in 1998 by an Italian group, which found that mouse BM cells could give rise to skeletal muscle cells when transplanted into a mouse muscle that had been damaged by an injection of a muscle toxin [3]; thus mouse BMSCs could migrate to sites of muscle injury and participate in muscle regeneration, albeit at low efficiency. From 1999 up to date it was reported that transplanted BM cells could produce hepatocytes [4–7], endothelial [8] and myocardial cells [9–11], central nervous system (CNS) neurons, and glial cells [12–14]. The reason why these forms of plasticity were not been seen before is probably due to the methods used. In earlier experiments, organ or tissue fragments were usually
Transdifferentiation-inducing HCCR-1 oncogene
Seon-Ah Ha, Hyun K Kim, JinAh Yoo, SangHee Kim, Seung M Shin, Youn S Lee, Soo Y Hur, Yong W Kim, Tae E Kim, Yeun J Chung, Shin S Jeun, Dong W Kim, Yong G Park, Jin Kim, Soon Y Shin, Young H Lee, Jin W Kim
BMC Cell Biology , 2010, DOI: 10.1186/1471-2121-11-49
Abstract: We report here that HCCR-1, previously shown to play an oncogenic role in human cancers, induces epithelial-to-mesenchymal transition (EMT) and mesenchymal-to-epithelial transition (MET) in human and mouse, respectively. The stem cell factor receptor CD117/c-Kit was induced in this transdifferentiated (EMT) sarcoma tissues. This MET occurring in HCCR-1 transfected cells is reminiscent of the transdifferentiation process during nephrogenesis. Indeed, expression of HCCR-1 was observed during the embryonic development of the kidney. This suggests that HCCR-1 might be involved in the transdifferentiation process of cancer stem cell.Therefore, we propose that HCCR-1 may be a regulatory factor that stimulates morphogenesis of epithelia or mesenchyme during neoplastic transformation.The concept that genetic events cooperate to achieve malignant transformation was proposed over a decade ago. Primary rodent cells are efficiently converted into tumorigenic cells by the co-expression of cooperating oncogenes. However, similar experiments with human cells have consistently failed [1]. In 1999, after more than 15 years of trying, researchers have managed to convert normal human cells into tumor cells by delivering telomerase catalytic subunit in combination with two oncogenes [2]. Although malignant transformation of human cells by a single oncogene may not occur or may require specialized factors, we demonstrated that HCCR-1, associated with various types of human cancers, alone induced tumorigenic conversion of mouse cells [3].We have identified a novel oncogene, human cervical cancer oncogene (HCCR), that was classified into 2 types: HCCR-1 (GenBank accession number AF 195651) and HCCR-2 (GenBank accession number AF 315598) [3]. The HCCR-1 and HCCR-2 overexpressed cells were tumorigenic in nude mice and HCCR transgenic mice developed breast cancers and metastasis [3,4]. Also, HCCR-1 was overexpressed in various types of human malignancies and was found to regulate the p53 tum
p53 Plays a Role in Mesenchymal Differentiation Programs, in a Cell Fate Dependent Manner  [PDF]
Alina Molchadsky, Igor Shats, Naomi Goldfinger, Meirav Pevsner-Fischer, Melissa Olson, Ariel Rinon, Eldad Tzahor, Guillermina Lozano, Dov Zipori, Rachel Sarig, Varda Rotter
PLOS ONE , 2008, DOI: 10.1371/journal.pone.0003707
Abstract: Background The tumor suppressor p53 is an important regulator that controls various cellular networks, including cell differentiation. Interestingly, some studies suggest that p53 facilitates cell differentiation, whereas others claim that it suppresses differentiation. Therefore, it is critical to evaluate whether this inconsistency represents an authentic differential p53 activity manifested in the various differentiation programs. Methodology/Principal Findings To clarify this important issue, we conducted a comparative study of several mesenchymal differentiation programs. The effects of p53 knockdown or enhanced activity were analyzed in mouse and human mesenchymal cells, representing various stages of several differentiation programs. We found that p53 down-regulated the expression of master differentiation-inducing transcription factors, thereby inhibiting osteogenic, adipogenic and smooth muscle differentiation of multiple mesenchymal cell types. In contrast, p53 is essential for skeletal muscle differentiation and osteogenic re-programming of skeletal muscle committed cells. Conclusions These comparative studies suggest that, depending on the specific cell type and the specific differentiation program, p53 may exert a positive or a negative effect, and thus can be referred as a “guardian of differentiation” at large.
Dose-Dependent Effect of Estrogen Suppresses the Osteo-Adipogenic Transdifferentiation of Osteoblasts via Canonical Wnt Signaling Pathway  [PDF]
Bo Gao, Qiang Huang, Yan-Shui Lin, Bo-Yuan Wei, Yun-Shan Guo, Zhen Sun, Long Wang, Jing Fan, Hong-Yang Zhang, Yue-Hu Han, Xiao-Jie Li, Jun Shi, Jian Liu, Liu Yang, Zhuo-Jing Luo
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0099137
Abstract: Fat infiltration within marrow cavity is one of multitudinous features of estrogen deficiency, which leads to a decline in bone formation functionality. The origin of this fat is unclear, but one possibility is that it is derived from osteoblasts, which transdifferentiate into adipocytes that produce bone marrow fat. We examined the dose-dependent effect of 17β-estradiol on the ability of MC3T3-E1 cells and murine bone marrow-derived mesenchymal stem cell (BMMSC)-derived osteoblasts to undergo osteo-adipogenic transdifferentiation. We found that 17β-estradiol significantly increased alkaline phosphatase activity (P<0.05); calcium deposition; and Alp, Col1a1, Runx2, and Ocn expression levels dose-dependently. By contrast, 17β-estradiol significantly decreased the number and size of lipid droplets, and Fabp4 and PPARγ expression levels during osteo-adipogenic transdifferentiation (P<0.05). Moreover, the expression levels of brown adipocyte markers (Myf5, Elovl3, and Cidea) and undifferentiated adipocyte markers (Dlk1, Gata2, and Wnt10b) were also affected by 17β-estradiol during osteo-adipogenic transdifferentiation. Western blotting and immunostaining further showed that canonical Wnt signaling can be activated by estrogen to exert its inhibitory effect of osteo-adipogenesis. This is the first study to demonstrate the dose-dependent effect of 17β-estradiol on the osteo-adipogenic transdifferentiation of MC3T3-E1 cells and BMMSCs likely via canonical Wnt signaling. In summary, our results indicate that osteo-adipogenic transdifferentiation modulated by canonical Wnt signaling pathway in bone metabolism may be a new explanation for the gradually increased bone marrow fat in estrogen-inefficient condition.
Scribble Modulates the MAPK/Fra1 Pathway to Disrupt Luminal and Ductal Integrity and Suppress Tumour Formation in the Mammary Gland  [PDF]
Nathan J. Godde,Julie M. Sheridan,Lorey K. Smith,Helen B. Pearson,Kara L. Britt,Ryan C. Galea,Laura L. Yates,Jane E. Visvader,Patrick O. Humbert
PLOS Genetics , 2014, DOI: doi/10.1371/journal.pgen.1004323
Abstract: Polarity coordinates cell movement, differentiation, proliferation and apoptosis to build and maintain complex epithelial tissues such as the mammary gland. Loss of polarity and the deregulation of these processes are critical events in malignant progression but precisely how and at which stage polarity loss impacts on mammary development and tumourigenesis is unclear. Scrib is a core polarity regulator and tumour suppressor gene however to date our understanding of Scrib function in the mammary gland has been limited to cell culture and transplantation studies of cell lines. Utilizing a conditional mouse model of Scrib loss we report for the first time that Scrib is essential for mammary duct morphogenesis, mammary progenitor cell fate and maintenance, and we demonstrate a critical and specific role for Scribble in the control of the early steps of breast cancer progression. In particular, Scrib-deficiency significantly induced Fra1 expression and basal progenitor clonogenicity, which resulted in fully penetrant ductal hyperplasia characterized by high cell turnover, MAPK hyperactivity, frank polarity loss with mixing of apical and basolateral membrane constituents and expansion of atypical luminal cells. We also show for the first time a role for Scribble in mammalian spindle orientation with the onset of mammary hyperplasia being associated with aberrant luminal cell spindle orientation and a failure to apoptose during the final stage of duct tubulogenesis. Restoring MAPK/Fra1 to baseline levels prevented Scrib-hyperplasia, whereas persistent Scrib deficiency induced alveolar hyperplasia and increased the incidence, onset and grade of mammary tumours. These findings, based on a definitive genetic mouse model provide fundamental insights into mammary duct maturation and homeostasis and reveal that Scrib loss activates a MAPK/Fra1 pathway that alters mammary progenitor activity to drive premalignancy and accelerate tumour progression.
Effects of twist over-expression on the transdifferentiation of human peritoneal mesothelial cells  [cached]
Cui-xiang LI,Shi-ren SUN,Li-jie HE,Rui DU
Medical Journal of Chinese People's Liberation Army , 2011,
Abstract: Objective To explore the effects of twist over-expression on the transdifferentiation of human peritoneal mesothelial cells(HPMCs).Methods The HPMCs were treated separately with 50mmol/L(high glucose group) and 5.6mmol/L(control group) D-glucose for 48h.The protein expression of twist,E-cadherin,Fsp1 and α-SMA were detected by Western blotting.The mRNA and protein expression of twist,E-cadherin,Fsp1 and α-SMA were tested by qRT-PCR and Western blotting after transfecting the plasmids pcDNA3.1-twist and empty vector pcDNA3.1 into HPMCs with Lipofectamine 2000 in vitro.The protein expression of twist,E-cadherin,Fsp1 and α-SMA were tested by Western blotting after silencing the twist expression by siRNA,empty vector pSlience and the parental cells.Results Compared with control group,the expression of twist,Fsp1 and α-SMA increased,and of E-cadherin decreased in high glucose group(P < 0.05).Compared with the empty vector group,after the over-expression of twist in HPMCs,the expression of E-cadherin decreased,and of Fsp1 and α-SMA increased in high glucose group(P < 0.05).Silencing the twist expression by siRNA,the expression of E-cadherin increased and of α-SMA and Fsp1 decreased in siTwist transfacted cells compared with pSlicencer-transfacted cell and parental cells(P < 0.05),and finally reversed the phenotype of MMT.Conclusion The over-expression of twist may promote the mesothelial-to-mesenchymal transition of HPMCs.
Epigenetic Regulation of B Lymphocyte Differentiation, Transdifferentiation, and Reprogramming  [PDF]
Bruna Barneda-Zahonero,Lidia Roman-Gonzalez,Olga Collazo,Tokameh Mahmoudi,Maribel Parra
Comparative and Functional Genomics , 2012, DOI: 10.1155/2012/564381
Abstract: B cell development is a multistep process that is tightly regulated at the transcriptional level. In recent years, investigators have shed light on the transcription factor networks involved in all the differentiation steps comprising B lymphopoiesis. The interplay between transcription factors and the epigenetic machinery involved in establishing the correct genomic landscape characteristic of each cellular state is beginning to be dissected. The participation of “epigenetic regulator-transcription factor” complexes is also crucial for directing cells during reprogramming into pluripotency or lineage conversion. In this context, greater knowledge of epigenetic regulation during B cell development, transdifferentiation, and reprogramming will enable us to understand better how epigenetics can control cell lineage commitment and identity. Herein, we review the current knowledge about the epigenetic events that contribute to B cell development and reprogramming.
Widespread Lichen Nitidus  [cached]
Singh Inderpal,Mehta Swami Das,Kanwar A. J
Indian Journal of Dermatology , 1997,
Abstract: An interesting case of widespread liched nitidus in a child is reported.
Cyclosporin A-induced gingival overgrowth is not associated with myofibroblast transdifferentiation
Sobral, Lays Martin;Kellermann, Michele Gassen;Graner, Edgard;Martelli-Junior, Hercilio;Coletta, Ricardo Della;
Brazilian Oral Research , 2010, DOI: 10.1590/S1806-83242010000200010
Abstract: cyclosporin a (cya) induces gingival overgrowth via its stimulatory effects on expression of transforming growth factor-beta1 (tgf-β1) and collagen. it is not known whether cya has a direct effect on gingival fibroblasts or induces its effect indirectly via stimulation of myofibroblast transdifferentiation. the present study was undertaken to examine the in vivo and in vitro effect of cya on myofibroblast transdifferentiation. rats were treated for 60 days with a daily subcutaneous injection of cya, and the gingival overgrowth tissue was analyzed by immunohistochemistry. in vitro, fibroblasts from normal gingiva (ng) were cultured in the presence of different concentrations of cya, and subjected to semi-quantitative reverse transcriptase-polymerase chain reaction and western blot. although cya treatment stimulated tgf-β1 expression by ng fibroblasts, it lacked to induce expression and production of isoform α of smooth muscle actin (α-sma), the specific myofibroblast marker. the expression levels of connective tissue growth factor (ctgf), which has been considered a key molecule to promote the transdifferentiation of myofibroblasts via tgf-β1 activation, were unaffected by cya. our results demonstrate that cya-induced gingival overgrowth is not associated with activation of myofibroblast transdifferentiation, since cya is not capable to increase ctgf expression.
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