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Defu Zeng - One of the best experts on this subject based on the ideXlab platform.
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reversal of autoimmunity by mixed chimerism enables reactivation of β cells and Transdifferentiation of α cells in diabetic nod mice
Proceedings of the National Academy of Sciences of the United States of America, 2020Co-Authors: Shanshan Tang, Mingfeng Zhang, Pere Santamaria, Arthur D Riggs, Liang Jin, Samuel Zeng, Yaxun Huang, Melissa Qin, Ubaydah Nasri, Defu ZengAbstract:Type 1 diabetes (T1D) results from the autoimmune destruction of β cells, so cure of firmly established T1D requires both reversal of autoimmunity and restoration of β cells. It is known that β cell regeneration in nonautoimmune diabetic mice can come from differentiation of progenitors and/or Transdifferentiation of α cells. However, the source of β cell regeneration in autoimmune nonobese diabetic (NOD) mice remains unclear. Here, we show that, after reversal of autoimmunity by induction of haploidentical mixed chimerism, administration of gastrin plus epidermal growth factor augments β cell regeneration and normalizes blood glucose in the firmly established diabetic NOD mice. Using transgenic NOD mice with inducible lineage-tracing markers for insulin-producing β cells, Sox9+ ductal progenitors, Nestin+ mesenchymal stem cells, and glucagon-producing α cells, we have found that both reactivation of dysfunctional low-level insulin expression (insulinlo) β cells and neogenesis contribute to the regeneration, with the latter predominantly coming from Transdifferentiation of α cells. These results indicate that, after reversal of autoimmunity, reactivation of β cells and Transdifferentiation of α cells can provide sufficient new functional β cells to reach euglycemia in firmly established T1D.
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260 or Transdifferentiation of a cells and redifferentiation of insulinlo s cells dominate s cell regeneration in late stage diabetic nod mice cured with induction of mixed chimerism and administration of gastrin and epidermal growth factor
Diabetes, 2020Co-Authors: Shanshan Tang, Mingfeng Zhang, Pere Santamaria, Arthur D Riggs, Liang Jin, Defu ZengAbstract:Type 1 diabetes (T1D) results from the autoimmune destruction of β cells. Cure of established T1D requires both reversal of autoimmunity and regeneration of β cells. Autoimmune NOD mice closely resemble human T1D. We have reported that administration of gastrin and epidermal growth factor (GE) allows β cell regeneration and cure of late-stage T1D in NOD mice after reversal of autoimmunity by induction of MHC-mismatched mixed chimerism. β cell regeneration in non-autoimmune diabetic mice can come from differentiation of Sox9+ pancreatic ductal progenitors, parenchymal progenitors, and Transdifferentiation of α cells. However, the source of β cell regeneration in autoimmune NOD mice remains unclear. Using NOD mice with inducible Sox9-EGFP, we found that Sox9+ pancreatic ductal progenitors only accounted for a small fraction of total β cell regeneration. Using Nestin-EGFP mice, we did not see any β cells originating from Nestin+ parenchymal progenitor cells. Using NOD mice with inducible glucagon-RFP, we found that ∼50% of regenerated β cells were from α cell Transdifferentiation in mice after induction of mixed chimerism and GE, although mixed chimerism alone induced few α to β cell Transdifferentiation in mice. In addition, using NOD mice with inducible insulin-EGFP, we found that the majority of residual β cells in late-stage diabetic NOD mice were insulinlo, and they became insulinhi after induction of mixed chimerism and GE treatment. Taken together, Transdifferentiation of α to β cells and re-differentiation of insulinlo cells are the major sources of β cell regeneration in late-stage diabetic NOD mice after induction of mixed chimerism and administration of GE. How hyperglycemia and GE differentially regulate α cell Transdifferentiation and β cell re-differentiation is under investigation. This work is supported by the Wanek Family fund. Disclosure S. Tang: None. M. Zhang: None. P. Santamaria: Board Member; Self; Parvus Therapeutics. A.D. Riggs: None. L. Jin: None. D. Zeng: None. Funding Todd and Karen Wanek Family Foundation Ltd.
Panagiotis A. Tsonis - One of the best experts on this subject based on the ideXlab platform.
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molecular signatures that correlate with induction of lens regeneration in newts lessons from proteomic analysis
Human Genomics, 2014Co-Authors: Konstantinos Sousounis, Mario Looso, Thomas Braun, Rital B. Bhavsar, Marcus Kruger, Jessica L Beebe, Panagiotis A. TsonisAbstract:Amphibians have the remarkable ability to regenerate missing body parts. After complete removal of the eye lens, the dorsal but not the ventral iris will transdifferentiate to regenerate an exact replica of the lost lens. We used reverse-phase nano-liquid chromatography followed by mass spectrometry to detect protein concentrations in dorsal and ventral iris 0, 4, and 8 days post-lentectomy. We performed gene expression comparisons between regeneration and intact timepoints as well as between dorsal and ventral iris. Our analysis revealed gene expression patterns associated with the ability of the dorsal iris for Transdifferentiation and lens regeneration. Proteins regulating gene expression and various metabolic processes were enriched in regeneration timepoints. Proteins involved in extracellular matrix, gene expression, and DNA-associated functions like DNA repair formed a regeneration-related protein network and were all up-regulated in the dorsal iris. In addition, we investigated protein concentrations in cultured dorsal (Transdifferentiation-competent) and ventral (Transdifferentiation-incompetent) iris pigmented epithelial (IPE) cells. Our comparative analysis revealed that the ability of dorsal IPE cells to keep memory of their tissue of origin and Transdifferentiation is associated with the expression of proteins that specify the dorso-ventral axis of the eye as well as with proteins found highly expressed in regeneration timepoints, especially 8 days post-lentectomy. The study deepens our understanding in the mechanism of regeneration by providing protein networks and pathways that participate in the process.
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Oocyte-type linker histone B4 is required for Transdifferentiation of somatic cells in vivo
The FASEB Journal, 2010Co-Authors: Nobuyasu Maki, Katia Del Rio-tsonis, Rinako Suetsugu-maki, Shozo Sano, Keita Ohsumi, Hiroshi Tarui, Kenta Nakamura, Osamu Nishimura, Panagiotis A. TsonisAbstract:The ability to reprogram in vivo a somatic cell after differentiation is quite limited. One of the most impressive examples of such a process is Transdifferentiation of pigmented epithelial cells (PECs) to lens cells during lens regeneration in newts. However, very little is known of the molecular events that allow newt cells to transdifferentiate. Histone B4 is an oocyte-type linker histone that replaces the somatic-type linker histone H1 during reprogramming mediated by somatic cell nuclear transfer (SCNT). We found that B4 is expressed and required during Transdifferentiation of PECs. Knocking down of B4 decreased proliferation and increased apoptosis, which resulted in considerable smaller lens. Furthermore, B4 knockdown altered gene expression of key genes of lens differentiation and nearly abolished expression of γ-crystallin. These data are the first to show expression of oocyte-type linker histone in somatic cells and its requirement in newt lens Transdifferentiation and suggest that transdifferen...
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regeneration via Transdifferentiation the lens and hair cells
Hearing Research, 2007Co-Authors: Panagiotis A. TsonisAbstract:Tissue repair and regeneration is mediated by mainly two strategies, the one employing the services of reserve cells and the other via Transdifferentiation of already differentiated somatic cells. In this mini-review some issues of Transdifferentiation will be presented, especially as they pertain to regeneration and induction of lens and hair cells in several animal models.
Shanshan Tang - One of the best experts on this subject based on the ideXlab platform.
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reversal of autoimmunity by mixed chimerism enables reactivation of β cells and Transdifferentiation of α cells in diabetic nod mice
Proceedings of the National Academy of Sciences of the United States of America, 2020Co-Authors: Shanshan Tang, Mingfeng Zhang, Pere Santamaria, Arthur D Riggs, Liang Jin, Samuel Zeng, Yaxun Huang, Melissa Qin, Ubaydah Nasri, Defu ZengAbstract:Type 1 diabetes (T1D) results from the autoimmune destruction of β cells, so cure of firmly established T1D requires both reversal of autoimmunity and restoration of β cells. It is known that β cell regeneration in nonautoimmune diabetic mice can come from differentiation of progenitors and/or Transdifferentiation of α cells. However, the source of β cell regeneration in autoimmune nonobese diabetic (NOD) mice remains unclear. Here, we show that, after reversal of autoimmunity by induction of haploidentical mixed chimerism, administration of gastrin plus epidermal growth factor augments β cell regeneration and normalizes blood glucose in the firmly established diabetic NOD mice. Using transgenic NOD mice with inducible lineage-tracing markers for insulin-producing β cells, Sox9+ ductal progenitors, Nestin+ mesenchymal stem cells, and glucagon-producing α cells, we have found that both reactivation of dysfunctional low-level insulin expression (insulinlo) β cells and neogenesis contribute to the regeneration, with the latter predominantly coming from Transdifferentiation of α cells. These results indicate that, after reversal of autoimmunity, reactivation of β cells and Transdifferentiation of α cells can provide sufficient new functional β cells to reach euglycemia in firmly established T1D.
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260 or Transdifferentiation of a cells and redifferentiation of insulinlo s cells dominate s cell regeneration in late stage diabetic nod mice cured with induction of mixed chimerism and administration of gastrin and epidermal growth factor
Diabetes, 2020Co-Authors: Shanshan Tang, Mingfeng Zhang, Pere Santamaria, Arthur D Riggs, Liang Jin, Defu ZengAbstract:Type 1 diabetes (T1D) results from the autoimmune destruction of β cells. Cure of established T1D requires both reversal of autoimmunity and regeneration of β cells. Autoimmune NOD mice closely resemble human T1D. We have reported that administration of gastrin and epidermal growth factor (GE) allows β cell regeneration and cure of late-stage T1D in NOD mice after reversal of autoimmunity by induction of MHC-mismatched mixed chimerism. β cell regeneration in non-autoimmune diabetic mice can come from differentiation of Sox9+ pancreatic ductal progenitors, parenchymal progenitors, and Transdifferentiation of α cells. However, the source of β cell regeneration in autoimmune NOD mice remains unclear. Using NOD mice with inducible Sox9-EGFP, we found that Sox9+ pancreatic ductal progenitors only accounted for a small fraction of total β cell regeneration. Using Nestin-EGFP mice, we did not see any β cells originating from Nestin+ parenchymal progenitor cells. Using NOD mice with inducible glucagon-RFP, we found that ∼50% of regenerated β cells were from α cell Transdifferentiation in mice after induction of mixed chimerism and GE, although mixed chimerism alone induced few α to β cell Transdifferentiation in mice. In addition, using NOD mice with inducible insulin-EGFP, we found that the majority of residual β cells in late-stage diabetic NOD mice were insulinlo, and they became insulinhi after induction of mixed chimerism and GE treatment. Taken together, Transdifferentiation of α to β cells and re-differentiation of insulinlo cells are the major sources of β cell regeneration in late-stage diabetic NOD mice after induction of mixed chimerism and administration of GE. How hyperglycemia and GE differentially regulate α cell Transdifferentiation and β cell re-differentiation is under investigation. This work is supported by the Wanek Family fund. Disclosure S. Tang: None. M. Zhang: None. P. Santamaria: Board Member; Self; Parvus Therapeutics. A.D. Riggs: None. L. Jin: None. D. Zeng: None. Funding Todd and Karen Wanek Family Foundation Ltd.
David J Nikolicpaterson - One of the best experts on this subject based on the ideXlab platform.
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advanced glycation end products cause epithelial myofibroblast Transdifferentiation via the receptor for advanced glycation end products rage
Journal of Clinical Investigation, 2001Co-Authors: Matthew D Oldfield, David J Nikolicpaterson, Leon A Bach, Josephine M Forbes, Anne Mcrobert, Vicki Thallas, Robert C Atkins, Tanya M Osicka, George Jerums, Mark E CooperAbstract:Tubulointerstitial disease, a prominent phenomenon in diabetic nephropathy, correlates with decline in renal function. The underlying pathogenic link between chronic hyperglycemia and the development of tubulointerstitial injury has not been fully elucidated, but myofibroblast formation represents a key step in the development of tubulointerstitial fibrosis. RAGE, the receptor for advanced glycation end products (AGEs), induces the expression of TGF-beta and other cytokines that are proposed to mediate the Transdifferentiation of epithelial cells to form myofibroblasts. Here we report specific binding of (125)I-AGE-BSA to cell membranes prepared from a rat proximal tubule cell line and show that the binding site was RAGE. AGE exposure induced dose-dependent epithelial-myofibroblast Transdifferentiation determined by morphological changes, de novo alpha smooth-muscle actin expression, and loss of epithelial E-cadherin staining. These effects could be blocked with neutralizing Ab's to RAGE or to TGF-beta. Transdifferentiation was also apparent in the proximal tubules of diabetic rats and in a renal biopsy from a patient with type 1 diabetes. The AGE cross-link breaker, phenyl-4,5-dimethylthiazolium bromide (ALT 711) reduced Transdifferentiation in diabetic rats in association with reduced tubular AGE and TGF-beta expression. This study provides a novel mechanism to explain the development of tubulointerstitial disease in diabetic nephropathy and provides a new treatment target.
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transforming growth factor β regulates tubular epithelial myofibroblast Transdifferentiation in vitro
Kidney International, 1999Co-Authors: Junming Fan, David J Nikolicpaterson, Robert C Atkins, Prudence A Hill, Hui Y LanAbstract:Transforming growth factor-β regulates tubular epithelial-myofibroblast Transdifferentiation in vitro. Background We recently found evidence of tubular epithelial-myofibroblast Transdifferentiation (TEMT) during the development of tubulointerstitial fibrosis in the rat remnant kidney. This study investigated the mechanisms that induce TEMT in vitro. Methods The normal rat kidney tubular epithelial cell line (NRK52E) was cultured for six days on plastic or collagen type I-coated plates in the presence or absence of recombinant transforming growth factor-β1 (TGF-β1). Transdifferentiation of tubular cells into myofibroblasts was assessed by electron microscopy and by expression of α-smooth muscle actin (α-SMA) and E-cadherin. Results NRK52E cells cultured on plastic or collagen-coated plates showed a classic cobblestone morphology. Culture in 1 ng/ml TGF-β caused only very minor changes in morphology, but culture in 10 or 50 ng/ml TGF-β1 caused profound changes. This involved hypertrophy, a loss of apical-basal polarity and microvilli, with cells becoming elongated and invasive, the formation of a new front-end back-end polarity, and the appearance of actin microfilaments and dense bodies. These morphological changes were accompanied by phenotypic changes. Double immunohistochemistry staining showed that the addition of TGF-β1 to confluent cell cultures caused a loss of the epithelial marker E-cadherin and de novo expression of α-SMA. An intermediate stage in Transdifferentiation could be seen with hypertrophic cells expressing both E-cadherin and α-SMA. De novo α-SMA expression was confirmed by Northern blotting, Western blotting, and flow cytometry. In particular, cells with a transformed morphology showed strong α-SMA immunostaining of characteristic microfilament structures along the cell axis. There was a dose-dependent increase in the percentage of cells expressing α-SMA with increasing concentrations of TGF-β1, which was completely inhibited by the addition of a neutralizing anti–TGF-β1 antibody. Compared with growth on plastic, cell culture on collagen-coated plates showed a threefold increase in the percentage of cells expressing α-SMA in response to TGF-β1. Conclusion TGF-β1 is a key mediator that regulates, in a dose-dependent fashion, Transdifferentiation of tubular epithelial cells into α-SMA+ myofibroblasts. This Transdifferentiation is markedly enhanced by growth on collagen type I. These findings have identified a novel pathway that may contribute to renal fibrosis associated with overexpression of TGF-β1 within the diseased kidney.
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tubular epithelial myofibroblast Transdifferentiation in progressive tubulointerstitial fibrosis in 5 6 nephrectomized rats
Kidney International, 1998Co-Authors: David J Nikolicpaterson, Tungpo Huang, Wuchang Yang, Zhengping Chen, Anhang YangAbstract:Tubular epithelial-myofibroblast Transdifferentiation in progressive tubulointerstitial fibrosis in 5/6 nephrectomized rats. Background Tubulointerstitial fibrosis is the final common pathway to end-stage renal failure. The present study investigated the potential role of tubular epithelial cells (TEC) in progressive fibrosis in the rat remnant kidney model. Methods Rats underwent 5/6 nephrectomy or a sham operation (control), and groups of six animals were killed at weeks 1, 3, 5, 9, 13, 17 and 21. Results Immunohistochemistry staining and in situ hybridization at week 3 after nephrectomy demonstrated de novo expression of alpha-smooth muscle actin ( α -SMA)–a marker of smooth muscle cells and myofibroblasts–by TEC that was invariably associated with disruption of the tubular basement membrane (TBM). This phenotypic evidence of tubular epithelial-myofibroblast Transdifferentiation was supported by ultrastructural studies identifying the presence of characteristic actin microfilaments and dense bodies within TEC with a transformed morphology. In the late stage of this apparent tubular epithelial-myofibroblast Transdifferentiation, TEC lost apical-basal polarity and tight junctions, became elongated, detached from the TBM, separated from neighboring cells and appeared to migrate into the peritubular interstitium through the damaged basement membrane. Indeed, focal peritubular accumulation of α -SMA + myofibroblasts and local tubulointerstitial fibrosis was closely associated with α -SMA + tubules, suggesting a tubular epithelial origin for some of these cells. Quantitative analysis found a significant correlation between the number of α -SMA + TEC and the accumulation of interstitial α -SMA + myofibroblasts and the severity of tubulointerstitial fibrosis (both P Conclusions This study provides phenotypic and morphological evidence to support the hypothesis that TEC are pro-fibrogenitor cells capable of tubular epithelial-myofibroblast Transdifferentiation in progressive renal fibrosis. In addition, we postulate that disruption of the TBM, which facilitates epithelial cell contact with the interstitial matrix, promotes this process of Transdifferentiation.
Takashi Kamatani - One of the best experts on this subject based on the ideXlab platform.
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upregulation of fgf9 in lung adenocarcinoma Transdifferentiation to small cell lung cancer
Cancer Research, 2021Co-Authors: Kota Ishioka, Hiroyuki Yasuda, Junko Hamamoto, Hideki Terai, Katsura Emoto, Taejung Kim, Shigemichi Hirose, Takashi KamataniAbstract:Transdifferentiation of lung adenocarcinoma to small cell lung cancer (SCLC) has been reported in a subset of lung cancer cases that bear EGFR mutations. Several studies have reported the prerequisite role of TP53 and RB1 alterations in Transdifferentiation. However, the mechanism underlying Transdifferentiation remains understudied, and definitive additional events, the third hit, for Transdifferentiation have not yet been identified. In addition, no prospective experiments provide direct evidence for Transdifferentiation. In this study, we show that FGF9 upregulation plays an essential role in Transdifferentiation. An integrative omics analysis of paired tumor samples from a patient with transdifferentiated SCLC exhibited robust upregulation of FGF9. Furthermore, FGF9 upregulation was confirmed at the protein level in four of six (66.7%) paired samples. FGF9 induction transformed mouse lung adenocarcinoma-derived cells to SCLC-like tumors in vivo through cell autonomous activation of the FGFR pathway. In vivo treatment of transdifferentiated SCLC-like tumors with the pan-FGFR inhibitor AZD4547 inhibited growth. In addition, FGF9 induced neuroendocrine differentiation, a pathologic characteristic of SCLC, in established human lung adenocarcinoma cells. Thus, the findings provide direct evidence for FGF9-mediated SCLC Transdifferentiation and propose the FGF9-FGFR axis as a therapeutic target for transdifferentiated SCLC. SIGNIFICANCE: This study demonstrates that FGF9 plays a role in the Transdifferentiation of lung adenocarcinoma to small cell lung cancer.
