scholarly journals PBF, a proto-oncogene in esophageal carcinoma

Open Medicine ◽  
2019 ◽  
Vol 14 (1) ◽  
pp. 748-756
Author(s):  
Shi-hai Lian ◽  
Jun-ding Song ◽  
Yi Huang
Keyword(s):  
Cell Cycle ◽  
Esophageal Carcinoma ◽  
Cell Function ◽  
Function Analysis ◽  
Cell Phenotype ◽  
Down Regulation ◽  
Apoptosis Pathway ◽  
Related Cell ◽  
Rnai Technology

AbstractEmerging evidence shows that the pituitary tumour-transforming gene (PTTG)-binding factor (PBF) functions as a proto-oncogene in some tumors. However, the precise functions of PBF in tumorigenesis and its action mechanisms remain largely unknown. Here for the first time we demonstrated that PBF was associated with a tumor-related cell phenotype in esophageal carcinoma (ESCA) and identified the involved signaling pathways. PBF was up-regulated in ESCA tissues (Data from GEPIA) and cells. Then we down-regulated PBF in ESCA cell lines, Eca-109 and TE-1, by using RNAi technology. Cell function analysis suggested that down-regulation of PBF could inhibit tumor-related cell phenotypes, including proliferation, motility, apoptosis and cell cycle, in Eca-109 and TE-1 cells. Mechanism investigation suggested that apoptosis induced by PBF knockdown may be mediated by the activation of the mitochondrial apoptosis pathway and cell cycle arrest. AKT/mTOR and Wnt3a/β-catenin, key pathways in regulating tumor proliferation and metastasis, were found to be inactivated by the down-regulation of PBF in ESCA cells. In conclusion, our study demonstrates that PBF functions as a proto-oncogene in ESCA in vitro, which may be mediated through AKT/mTOR and Wnt3a/β-catenin pathways.

scholarly journals Reversibility of hAT-MSCs phenotypic and metabolic changes after exposure to and withdrawal from HCC-conditioned medium through regulation of the ROS/MAPK/HIF-1α signaling pathway

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Chenyang Wang ◽  
Jie Hu ◽  
Zheng Chen ◽  
Yifan Wang ◽  
Sinan Lu ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Glucose Metabolism ◽  
Conditioned Medium ◽  
Signaling Pathway ◽  
Tumor Therapy ◽  
Migration And Invasion ◽  
Cell Phenotype ◽  
Apoptosis Pathway ◽  
Secretory Phenotype

Abstract Background Mesenchymal stem cells (MSCs) play an important role in tumor progression; concomitantly, MSCs also undergo profound changes in the tumor microenvironment (TME). These changes can directly impact the application and efficacy of MSC-based anti-tumor therapy. However, few studies have focused on the regulation of MSC fate in TME, which will limit the progress of MSC-based anti-tumor therapy. Herein, we investigated the effects of conditioned medium from human hepatocellular carcinoma cells (HCC-CM) on the phenotype and glucose metabolism of human adipose tissue-derived MSCs (hAT-MSCs). Methods The passage 2 (P2) to passage 3 (P3) hAT-MSCs were exposed to conditioned medium from Hep3B, Huh7 and HCCLM3 cells for 4–8 weeks in vitro. Then, immunofluorescent, CCK-8 assay, EdU assay, Transwell assay, and flow cytometry were used to assess the alterations in cell phenotype in terms of cell morphology, secretory profiles, proliferation, migration, invasion, cell cycle, and apoptosis. In addition, glucose metabolism was evaluated by related kits. Next, the treated hAT-MSCs were subjected to withdrawal from HCC-CM for 2–4 weeks, and alterations in phenotype and glucose metabolism were reevaluated. Finally, the molecular mechanism was clarified by Western blotting. Results The results revealed that after exposure to HCC-CM, hAT-MSCs developed a stellate-shaped morphology. In association with cytoskeleton remodeling, hAT-MSCs showed enhanced capacities for migration and invasion, while cell proliferation was inhibited by regulating the cell cycle by downregulating cyclins and cyclin-dependent kinases and activating the mitochondrial apoptosis pathway. In terms of glucose metabolism, our results showed mitochondrial dysfunction and elevated glycolysis of hAT-MSCs. However, interestingly, when the treated hAT-MSCs were subjected to withdrawal from HCC-CM, the alterations in phenotype and glucose metabolism could be reversed, but secretory phenotype and tumor-promoting properties appear to be permanent. Further studies showed that these changes in hAT-MSCs may be regulated by the ROS/MAPK/HIF-1α signaling pathway. Conclusion Taken together, the effects of long-term HCC-CM treatment on phenotype and glucose metabolism in hAT-MSCs are modest and largely reversible after withdrawal, but HCC-CM endow hAT-MSCs with permanent secretory phenotype and tumor-promoting properties. This is the first report on the reversal of phenotype and glucose metabolism in tumor-associated MSCs (TA-MSCs), it is anticipated that new insights into TA-MSCs will lead to the development of novel strategies for MSC-based anti-tumor therapy.

scholarly journals Reversibility of hAT-MSCs phenotypic and metabolic changes after exposure to and withdrawal form HCC-conditioned medium through regulation of the ROS/MAPK/HIF-1α signalling pathway

2020 ◽  
Author(s):  
Chenyang Wang ◽  
Jie Hu ◽  
Zheng Chen ◽  
Yifan Wang ◽  
Sinan Lu ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Glucose Metabolism ◽  
Conditioned Medium ◽  
Tumor Therapy ◽  
Signalling Pathway ◽  
Migration And Invasion ◽  
Cell Phenotype ◽  
Apoptosis Pathway ◽  
Secretory Phenotype

Abstract Background: Mesenchymal stem cells (MSCs) play an important role in tumor progression; concomitantly, MSCs also undergo profound changes in the tumor microenvironment (TME). These changes can directly impact the application and efficacy of MSC-based anti-tumor therapy. However, few studies have focused on the regulation of MSC fate in TME, which will limit the progress of MSC-based anti-tumor therapy. Herein, we investigated the effects of conditioned medium from human hepatocellular carcinoma cells (HCC-CM) on the phenotype and glucose metabolism of human adipose tissue-derived MSCs (hAT-MSCs). Methods: The passage 2 (P2) to passage 3 (P3) hAT-MSCs were exposed to conditioned medium from Hep3B, Huh7 and HCCLM3 cells for 4-8 weeks in vitro. Then, immunofluorescent, CCK-8 assay, EdU assay, Transwell assay, and flow cytometry were used to assess the alterations in cell phenotype in terms of cell morphology, secretory profiles, proliferation, migration, invasion, cell cycle, and apoptosis. In addition, glucose metabolism was evaluated by related kits. Next, the treated hAT-MSCs were subjected to withdrawal from HCC-CM for 2-4 weeks, and alterations in phenotype and glucose metabolism were reevaluated. Finally, the molecular mechanism was clarified by Western blotting. Results: The results revealed that after exposure to HCC-CM, hAT-MSCs developed a stellate-shaped morphology. In association with cytoskeleton remodelling, hAT-MSCs showed enhanced capacities for migration and invasion, while cell proliferation was inhibited by regulating the cell cycle by downregulating cyclins and cyclin-dependent kinases and activating the mitochondrial apoptosis pathway. In terms of glucose metabolism, our results showed mitochondrial dysfunction and elevated glycolysis of hAT-MSCs. However, interestingly, when the treated hAT-MSCs were subjected to withdrawal from HCC-CM, the alterations in phenotype and glucose metabolism could be reversed, but secretory phenotype and tumor-promoting properties appear to be permanent. Further studies showed that these changes in hAT-MSCs may be regulated by the ROS/MAPK/HIF-1α signalling pathway. Conclusion: Taken together, the effects of long-term HCC-CM treatment on phenotype and glucose metabolism in hAT-MSCs are modest and largely reversible after withdrawal, but HCC-CM endow hAT-MSCs with permanent secretory phenotype and tumor-promoting properties. This is the first report on the reversal of phenotype and glucose metabolism in tumor-associated MSCs (TA-MSCs), it is anticipated that new insights into TA-MSCs will lead to the development of novel strategies for MSC-based anti-tumor therapy.

scholarly journals Reversibility of hAT-MSCs phenotypic and metabolic changes after exposure to and withdrawal form HCC-conditioned medium through regulation of the ROS/MAPK/HIF-1α signalling pathway

2020 ◽  
Author(s):  
Chenyang Wang ◽  
Jie Hu ◽  
Zheng Chen ◽  
Yifan Wang ◽  
Sinan Lu ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Glucose Metabolism ◽  
Conditioned Medium ◽  
Tumor Therapy ◽  
Signalling Pathway ◽  
Migration And Invasion ◽  
Cell Phenotype ◽  
Apoptosis Pathway ◽  
Secretory Phenotype

Abstract Background: Mesenchymal stem cells (MSCs) play an important role in tumor progression; concomitantly, MSCs also undergo profound changes in the tumor microenvironment (TME). These changes can directly impact the application and efficacy of MSC-based anti-tumor therapy. However, few studies have focused on the regulation of MSC fate in TME, which will limit the progress of MSC-based anti-tumor therapy. Herein, we investigated the effects of conditioned medium from human hepatocellular carcinoma cells (HCC-CM) on the phenotype and glucose metabolism of human adipose tissue-derived MSCs (hAT-MSCs). Methods: The passage 2 (P2) to passage 3 (P3) hAT-MSCs were exposed to conditioned medium from Hep3B, Huh7 and HCCLM3 cells for 4-8 weeks in vitro. Then, immunofluorescent, CCK-8 assay, EdU assay, Transwell assay, and flow cytometry were used to assess the alterations in cell phenotype in terms of cell morphology, secretory profiles, proliferation, migration, invasion, cell cycle, and apoptosis. In addition, glucose metabolism was evaluated by related kits. Next, the treated hAT-MSCs were subjected to withdrawal from HCC-CM for 2-4 weeks, and alterations in phenotype and glucose metabolism were reevaluated. Finally, the molecular mechanism was clarified by Western blotting. Results: The results revealed that after exposure to HCC-CM, hAT-MSCs developed a stellate-shaped morphology. In association with cytoskeleton remodelling, hAT-MSCs showed enhanced capacities for migration and invasion, while cell proliferation was inhibited by regulating the cell cycle by downregulating cyclins and cyclin-dependent kinases and activating the mitochondrial apoptosis pathway. In terms of glucose metabolism, our results showed mitochondrial dysfunction and elevated glycolysis of hAT-MSCs. However, interestingly, when the treated hAT-MSCs were subjected to withdrawal from HCC-CM, the alterations in phenotype and glucose metabolism could be reversed, but secretory phenotype and tumor-promoting properties appear to be permanent. Further studies showed that these changes in hAT-MSCs may be regulated by the ROS/MAPK/HIF-1α signalling pathway. Conclusion: Taken together, the effects of long-term HCC-CM treatment on phenotype and glucose metabolism in hAT-MSCs are modest and largely reversible after withdrawal, but HCC-CM endow hAT-MSCs with permanent secretory phenotype and tumor-promoting properties. This is the first report on the reversal of phenotype and glucose metabolism in tumor-associated MSCs (TA-MSCs), it is anticipated that new insights into TA-MSCs will lead to the development of novel strategies for MSC-based anti-tumor therapy.

High GATA-2 expression inhibits human hematopoietic stem and progenitor cell function by effects on cell cycle

Blood ◽  
2009 ◽  
Vol 113 (12) ◽  
pp. 2661-2672 ◽  
Author(s):  
Alex J. Tipping ◽  
Cristina Pina ◽  
Anders Castor ◽  
Dengli Hong ◽  
Neil P. Rodrigues ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cord Blood ◽  
Cell Function ◽  
Ki 67 ◽  
Human Cord Blood ◽  
Hematopoietic Stem ◽  
Cord Blood Cells ◽  
Low Efficiency

Abstract Evidence suggests the transcription factor GATA-2 is a critical regulator of murine hematopoietic stem cells. Here, we explore the relation between GATA-2 and cell proliferation and show that inducing GATA-2 increases quiescence (G0 residency) of murine and human hematopoietic cells. In human cord blood, quiescent fractions (CD34+CD38−HoechstloPyronin Ylo) express more GATA-2 than cycling counterparts. Enforcing GATA-2 expression increased quiescence of cord blood cells, reducing proliferation and performance in long-term culture-initiating cell and colony-forming cell (CFC) assays. Gene expression analysis places GATA-2 upstream of the quiescence regulator MEF, but enforcing MEF expression does not prevent GATA-2–conferred quiescence, suggesting additional regulators are involved. Although known quiescence regulators p21CIP1 and p27KIP1 do not appear to be responsible, enforcing GATA-2 reduced expression of regulators of cell cycle such as CCND3, CDK4, and CDK6. Enforcing GATA-2 inhibited human hematopoiesis in vivo: cells with highest exogenous expression (GATA-2hi) failed to contribute to hematopoiesis in nonobese diabetic–severe combined immunodeficient (NOD-SCID) mice, whereas GATA-2lo cells contributed with delayed kinetics and low efficiency, with reduced expression of Ki-67. Thus, GATA-2 activity inhibits cell cycle in vitro and in vivo, highlighting GATA-2 as a molecular entry point into the transcriptional program regulating quiescence in human hematopoietic stem and progenitor cells.

Thrombin Enhances Spontaneous Tumor Growth and Cell Cycle Activation by Downregulation of p27Kip1 and Upregulation of Skp2 and MiR-222

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 396-396
Author(s):  
Liang Hu ◽  
Sherif Ibrahim ◽  
Cynthia Liu ◽  
Jeffrey Skaar ◽  
Michelle Pagano ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Growth Factors ◽  
Cell Growth ◽  
Tumor Growth ◽  
Tumor Cell ◽  
Tumor Volume ◽  
S Phase ◽  
Down Regulation

Abstract Although it has been generally accepted that hypercoagulability contributes to enhancing tumor growth via generation of thrombin (Cancer Cell10:355, 2006), it has not been rigorously proven, nor has the mechanism been established at the cell cycle level. Previous studies have employed thrombin-treated tumor cell lines in vitro and in vivo. In vitro studies were performed in the presence of serum which contains a panoply of growth factors. In vivo studies have used huge non-pathologic concentrations of tumor cells injected into the flank, organ or blood of a mouse. In these situations, tumor growth could be a result of thrombin-induced angiogenesis. We therefore employed a transgenic mouse prostate cancer model (TRAMP) programmed to develop prostate CA over a period of 140–175 days. We treated these animals with thrombin to induce hypercoagulability or hirudin to inhibit endogenous thrombin production, to determine whether thrombin regulates this process independent of angiogenesis. Repetitive thrombin injection enhanced prostate tumor volume 6–8 fold (p<0.04). Repetitive hirudin decreased tumor volume 13–24 fold (p<0.04) via its effect on generated endogenous thrombin, n=6. Thrombin enhanced the production of several vascular growth factors and receptors 2.5 – 3 fold in the liver (VEGF, KDR, ANG-2, Tie2, GRO-1, CD31) and enhanced angiogenesis in the liver, n=3–4. Thrombin had no effect on tumor angiogenesis. Thus, the thrombin-induced spontaneous tumor growth was independent of angiogenesis. We next turned our attention to cell cycle regulators in serum-starved (72 hr) Go-synchronized LNcap prostate CA cells, employing Brdu and Propidium iodide staining. Addition of thrombin (0.5 u/ml) or its PAR-1 receptor agonist, TFLLRN (100 uM) had the same effect as androgen containing serum, inducing cells to leave Go, enter G1 and progress to S-phase. At 8 hrs the number of S-phase cells increased dramatically for both the serum (29 fold) as well as thrombin-treated cells (48 fold), n=3. Similar observations were noted in a Glioblastoma cell line, T98G. We further analyzed the effect of thrombin by performing immunoblots on cell cycle components mediated during cell growth and proliferation. In synchronized Go cells, levels of p27Kip1, a cyclin-dependent kinase inhibitor are high, while levels of cyclins D1 and A, the activation subunits for cyclin-dependent kinases are low. Both thrombin or serum addition led to down-regulation of p27Kip1 with concomitant induction of Skp2, the E3 ubiquitin ligase for p27Kip1. Cyclins D1 and A are induced by similar kinetics, indicating entry into S-phase by 8 hrs. Since p27Kip1 appears to be a rate-limiting down-regulator of the cell cycle (absent with high tumor grade and predicts poor prognosis), we confirmed its role by testing the effect of thrombin or TFLLRN by transfecting p27Kip1 in LNcap cells. This transfection completely prevented the cell cycle stimulation induced by these agonists. A similar approach was used with Skp2 knock down (KD), a negative down-regulator of p27Kip1. KD of Skp2 (over expressed in numerous cancers) completely prevented cell cycle progression induced by thrombin/TFLLRN. MiRNA 222 (upregulated in many cancers) is another down-regulator of p27Kip1. Further analysis following thrombin treatment revealed a robust upregulation at 4 and 8 hrs, providing further proof for the role of thrombin in down-regulating p27Kip1 and stimulating tumor cell entrance into S-phase. Thus, 1) Thrombin enhances spontaneous prostate cell growth in vivo in the absence of enhanced angiogenesis; 2) Thrombin activates the tumor cell cycle by stimulating the down-regulation of p27Kip1 through the upregulation of Skp2 and MiRNA 222.

scholarly journals 2-Methoxyestradiol-bis-sulphamate disrupts microtubule network, arrests cell cycle and induces apoptosis in an esophageal carcinoma cell line

2012 ◽  
Vol 31 (1) ◽  
Author(s):  
T.V. Mqoco ◽  
Sumari Marais ◽  
Annie M. Joubert
Keyword(s):  
Cell Cycle ◽  
Esophageal Carcinoma ◽  
Cell Line ◽  
Anticancer Drug ◽  
Carcinoma Cell ◽  
In Vitro Studies ◽  
Carcinoma Cell Line ◽  
Microtubule Network

Future in vitro studies into the mechanism of this potentially anticancer drug are warranted.

scholarly journals Increased exosome secretion in neurons aging in vitro by NPC1-mediated endosomal cholesterol buildup

2021 ◽  
Vol 4 (8) ◽  
pp. e202101055
Author(s):  
Francesc X Guix ◽  
Ana Marrero Capitán ◽  
Álvaro Casadomé-Perales ◽  
Irene Palomares-Pérez ◽  
Inés López del Castillo ◽  
...  
Keyword(s):  
Extracellular Vesicles ◽  
Cell Function ◽  
Waste Material ◽  
Aging Brain ◽  
Multivesicular Bodies ◽  
Compensatory Mechanisms ◽  
Down Regulation

As neurons age, they show a decrease in their ability to degrade proteins and membranes. Because undegraded material is a source of toxic products, defects in degradation are associated with reduced cell function and survival. However, there are very few dead neurons in the aging brain, suggesting the action of compensatory mechanisms. We show in this work that ageing neurons in culture show large multivesicular bodies (MVBs) filled with intralumenal vesicles (ILVs) and secrete more small extracellular vesicles than younger neurons. We also show that the high number of ILVs is the consequence of the accumulation of cholesterol in MVBs, which in turn is due to decreased levels of the cholesterol extruding protein NPC1. NPC1 down-regulation is the consequence of a combination of upregulation of the NPC1 repressor microRNA 33, and increased degradation, due to Akt-mTOR targeting of NPC1 to the phagosome. Although releasing more exosomes can be beneficial to old neurons, other cells, neighbouring and distant, can be negatively affected by the waste material they contain.

scholarly journals PRMT5 Is Upregulated in Activated T Cells and Is a Novel Therapeutic Target for Acute Gvhd

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 2034-2034
Author(s):  
Parvathi Ranganathan ◽  
Katiri Snyder ◽  
Nina Zizter ◽  
Hannah K. Choe ◽  
Robert A Baiocchi ◽  
...  
Keyword(s):  
Cell Cycle ◽  
T Cells ◽  
T Cell ◽  
Western Blot ◽  
Cell Function ◽  
T Cell Proliferation ◽  
Activated T Cells ◽  
And Function

Abstract Introduction: Acute graft-versus-host disease (aGVHD), a T cell-mediated immunological disorder is the leading cause of non-relapse mortality in patients receiving allogeneic bone marrow transplants. Protein arginine methyltransferase 5 (PRMT5) catalyzes symmetric dimethylation (me2s) of arginine (R) residues on histones (primarily H3R8 and H3R4) and other proteins. PRMT5 is overexpressed in many leukemias and lymphomas, and epigenetic changes driven by PRMT5 lead to repression of tumor suppressors and promote growth and survival of cancer cells. Recently it was shown that T cells are sensitive to R-methylation and PRMT5 promotes activation of memory T helper cells. Here we investigate: 1) mechanisms by which PRMT5 regulates T cell function; and 2) PRMT5 inhibition as a therapeutic strategy for aGVHD. Materials and Methods: Splenic T cells were isolated from lethally irradiated B6D2F1 mice that received either T cell depleted bone marrow (TCD-BM) or TCD-BM with C57/BL6 (B6) allogeneic splenocytes on day 21 post-transplant. In vitro activation of B6 T cells was achieved with CD3/CD28 Dynabeads or co-culture with allogeneic BM-derived dendritic cells. PRMT5 expression (RT-PCR, western blot) and function (H3R8me2s western blot) were evaluated. PRT220, a novel inhibitor of PRMT5, was used to evaluate PRMT5 inhibition on T cell function in vitro and in vivo. We assessed T cell proliferation (Cell Trace Violet, Ki67), apoptosis (Annexin V), cytokine secretion (ELISA, flow cytometry), cell cycle (PI incorporation), and cell signaling (western blot). Lethally irradiated F1 recipients received TCD-BM only (10x106 cells) or TCD-BM + B6 splenocytes (20 x 106). Recipients of allogeneic splenocytes were treated with PRT220 (2mg/kg) or vehicle by oral gavage once weekly starting day 7 post-transplant. Mice were monitored for survival and clinical aGVHD scores. Results: PRMT5 expression and function is upregulated following T cell activation. Inhibition of PRMT5 reduces T cell proliferation and IFN-g secretion. PRMT5 inhibition in CD3/CD28 stimulated T cells results in disruption of multiple histone epigenetic marks, cell-cycle progression (via G1 arrest) and perturbation of ERK-MAPK signaling cascades. Finally, administration of PRT220 resulted in significantly prolonging the survival of allo-transplanted recipient mice (median survival, PRT220 vs. vehicle, 36.5 vs. 26 days, p=0.01). PRT220-treated recipients also exhibited significant lower aGVHD clinical (p<0.05), pathological scores (p<0.05) and lower serum TNF-a (p<0.05) and IFN-g (p<0.05) than vehicle-treated recipients. Conclusions: PRMT5 expression and function are upregulated in activated T cells. Inhibition of PRMT5 function using a novel and specific small-molecule inhibitor, PRT220, down-regulates T cells proliferative and effector response, induces cell-cycle arrest and perturbs signaling pathways. PRT220 shows potent biological activity in vivo by reducing aGVHD clinical severity and significantly prolonging survival in mouse models of aGVHD. Therefore, PRMT5 is a novel and druggable target for aGVHD. Disclosures No relevant conflicts of interest to declare.

scholarly journals In Vitro CSC-derived Cardiomyocytes Exhibit the Typical microRNA-mRNA Blueprint of Endogenous Cardiomyocytes

2021 ◽  
Author(s):  
Mariangela Scalise ◽  
Fabiola Marino ◽  
Luca Salerno ◽  
Mancuso Teresa ◽  
Donato Cappetta ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Regulators ◽  
Cardiomyocyte Differentiation ◽  
Down Regulation ◽  
Stem Cell Expansion ◽  
Cell Cycle Genes ◽  
Neonatal Cardiomyocytes ◽  
Gene Regulatory ◽  
Regulation Of Cell Cycle

Abstract miRNAs modulate cardiomyocyte specification in embryonic hearts and in pluripotent stem cells by targeting mRNAs of cell cycle regulators and acting in gene regulatory loops that complete commitment to the cardiac muscle lineage. It is still unknown if/to-what-extent these miRNA/mRNA networks are operative during cardiomyocyte differentiation of adult cardiac stem/progenitor cells (CSCs). Clonally-derived mouse CSCs differentiated into contracting cardiomyocytes in vitro (iCMs). RNASeq comparison of “CSCs vs. iCMs” mRNome and microRNome showed a balanced up-regulation of sarcomere and mitochondrial related mRNAs together with a down-regulation of cell cycle and DNA replication mRNAs. The down-regulation of cell cycle genes and the up-regulation of the mature myofilament genes in iCMs did not reach the levels of mouse terminally differentiated adult cardiomyocytes (aCMs), while they get to intermediate levels between those of fetal and neonatal cardiomyocytes. Cardiomyo-miRs were up-regulated in iCMs while those miRs positively regulating stem cell expansion and self-renewal were down-regulated. The specific networks of miRNA/mRNAs operative in iCMs closely resembled miRNA/mRNA networks of aCMs. Two of these miRs, miR-1 and miR-499, enhanced myogenic commitment toward terminal differentiation of iCMs. In conclusions, CSC specification/differentiation into contracting iCMs follows known cardiomyo-MiR-dependent developmental cardiomyocyte differentiation trajectories and iCMs transcriptome/miRNome resembles that of aCMs.

Sign in / Sign up

Export Citation Format

Share Document