Posts Tagged: regeneration

Endocardial Cell Plasticity in Cardiac Development, Diseases and Regeneration

Endocardial Cell Plasticity in Cardiac Development, Diseases and Regeneration

Hui Zhang, Kathy O. Lui, Bin Zhou

Mural cells derived from endocardium in developing heart. A and B, Endocardial cells undergo endothelial to mesenchymal transition to form PDGFRβ+PDGFRα+NG2– mesenchymal cells in the cardiac cushion (black arrows). C and D, Mesenchymal cells migrate into myocardium (white arrows) to form PDGFRβ+PDGFRα–NG2+αSMA+ smooth muscle cells or PDGFRβ+PDGFRα–NG2+αSMA– pericytes. [Powerpoint File]

Endocardial Cell Plasticity in Cardiac Development, Diseases and Regeneration

Endocardial Cell Plasticity in Cardiac Development, Diseases and Regeneration

Hui Zhang, Kathy O. Lui, Bin Zhou

Molecular regulation of endocardial cushion endothelial to mesenchymal transition (EndoMT). Multiple signaling pathways including BMP (bone morphogenetic protein), TGFβ (transforming growth factor-β), and Notch control endocardial contribution to cushion morphogenesis through regulating EndoMT. AVC indicates atrioventricular canal; Msx, msh homeobox; OFT, outflow tract; Rbpj, recombination signal binding protein for immunoglobulin kappa J region; Slug, snail family zinc finger 2; Snail, snail family zinc finger 1; and Twist, twist basic helix–loop–helix transcription factor. [Powerpoint File]

Endocardial Cell Plasticity in Cardiac Development, Diseases and Regeneration

Endocardial Cell Plasticity in Cardiac Development, Diseases and Regeneration

Hui Zhang, Kathy O. Lui, Bin Zhou

Schematic showing the endocardial cell plasticity. Endocardial cell (in the center) differentiates into hematopoietic cell, cushion mesenchyme, coronary, liver vascular endothelial cell, and cardiomyocyte (arrows). Question (?) indicates that the cardiomyocyte fate needs validated. Endocardial cell also contributes to fibroblast, adipocyte, pericyte, and smooth muscle cell (dotted arrows), which might be through intermediate stage of mesenchymal cell. [Powerpoint File]

Elixir of Life: Thwarting Aging With Regenerative Reprogramming

Elixir of Life: Thwarting Aging With Regenerative Reprogramming

Ergin Beyret, Paloma Martinez Redondo, Aida Platero Luengo, Juan Carlos Izpisua Belmonte

Regenerative reprogramming approaches. In vivo induction of transdifferentiation can be used to repopulate the cells lost during aging as an alternative to transplantation, complementing the intrinsic regenerative capacity. For instance, neurons lost to neurodegenerative diseases can be replaced by transdifferentiating resident glia or astrocytes; cardiac fibroblasts can be the cell source for induced cardiomyocytes; α, ductal, and acinar cells can be used for β cells. Alternatively, transient 4F (OCT4, KLF4, SOX2, and c-Myc) expression can be used to rejuvenate cells. This in turn can decelerate degeneration of biological units that have low regeneration capacity (eg, aorta) or augment regeneration capacity by counteracting stem cell exhaustion (eg, muscle) or by enhancing the plasticity of organs that intrinsically undergo cell conversions during regeneration (eg, transdifferentiation in the pancreas and dedifferentiation in the kidney). MuSC indicates muscle stem cell. [Powerpoint File]

Induced Pluripotent Stem Cells 10 Years Later For Cardiac Applications

Induced Pluripotent Stem Cells 10 Years Later: For Cardiac Applications

Yoshinori Yoshida, Shinya Yamanaka

Factors which possibly cause clonal differences of induced pluripotent stem cells (iPSCs). [Powerpoint File]

Induced Pluripotent Stem Cells 10 Years Later: For Cardiac Applications

Induced Pluripotent Stem Cells 10 Years Later: For Cardiac Applications

Yoshinori Yoshida, Shinya Yamanaka

Patient stratification based on drug responsiveness using induced pluripotent stem cells–derived cardiac myocytes. [Powerpoint File]

Multimodal Regulation of Cardiac Myocyte Proliferation

Multimodal Regulation of Cardiac Myocyte Proliferation

Xuejun Yuan, Thomas Braun

Schematic overview of cell-cycle activities, global DNA methylation, and metabolic properties of fetal, neonatal, adult, and hypertrophic cardiac myocytes. Green arrows represent cell-cycle processes leading to endomitosis and multinucleation, whereas orange arrows refer to endoreduplication resulting in polyploidy. cTnI (TNNI3) indicates cardiac troponin; FAO, fatty acid oxidation; and ssTnI(TNNI1), slow skeletal troponin. [Powerpoint File]

Multimodal Regulation of Cardiac Myocyte Proliferation

Multimodal Regulation of Cardiac Myocyte Proliferation

Xuejun Yuan, Thomas Braun

Schematic overview of the potential interplay between metabolic signals and epigenetic mechanisms for regulation of cardiac myocyte proliferation. Oxygen-dependent stimulation of mitochondrial respiration increases α-ketoglutarate (α-KG) production, which might stimulate DNA and histone demethylation thereby activating anti-proliferative genes or inducing accumulation of intracellular reactive oxygen species (ROS) and DNA damage responses. Such cues might promote polyplodization and/or activation of Hippo signaling prompting cell-cycle exit. In contrast, hypoxia stabilizes HIF1α (hypoxia-inducible factor 1-alpha) and leads to accumulation of intermediate metabolites such as succinate and fumarate, which inhibit α-KG–dependent epigenetic modifiers including TETs (ten–eleven translocation) and histone demethylases (HDMs) and stabilize HIF1α thus activating proproliferative gene programs. In addition, fumarate activates the Nrf2/Pitx2/Yap1 axis, which positively regulates proproliferative gene programs. Dashed lines indicate regulatory cascades investigated in noncardiac myocytes. [Powerpoint File]

Emerging Concepts in Paracrine Mechanisms in Regenerative Cardiovascular Medicine and Biology

Emerging Concepts in Paracrine Mechanisms in Regenerative Cardiovascular Medicine and Biology

Conrad P. Hodgkinson, Akshay Bareja, José A. Gomez, Victor J. Dzau

Paracrine factors affect different temporal events after myocardial injury influencing different stages of the reparative and regenerative processes. [Powerpoint File]

Emerging Concepts in Paracrine Mechanisms in Regenerative Cardiovascular Medicine and Biology

Emerging Concepts in Paracrine Mechanisms in Regenerative Cardiovascular Medicine and Biology

Conrad P. Hodgkinson, Akshay Bareja, José A. Gomez, Victor J. Dzau

Paracrine factors affect different cell types and create a microenvironment that is influenced by concentration gradients, with temporal and spatial summation of cellular responses. Reprinted from Hodgkinson et al149 with permission of the publisher. Copyright ©2015, Elsevier. [Powerpoint File]

Emerging Concepts in Paracrine Mechanisms in Regenerative Cardiovascular Medicine and Biology

Emerging Concepts in Paracrine Mechanisms in Regenerative Cardiovascular Medicine and Biology

Conrad P. Hodgkinson, Akshay Bareja, José A. Gomez, Victor J. Dzau

Paracrine factors are pleiotropic. For illustration, we show the cellular effects of 2 selective paracrine factors on the cardiomyocyte. Left, Hypoxic-induced Akt regulated stem cell factor (HASF) and secreted frizzled related protein 2 (Sfrp2) inhibit cardiomyocyte apoptosis through divergent pathways. HASF, after binding to a growth factor receptor, inhibits cytochrome release from mitochondria via protein kinase C-ε (PKCε). In contrast, Sfrp2 inhibits Wnt activation of frizzled receptors. This induces β-catenin degradation via the anaphase promoting complex (APC) complex. Right, Abi3bp and Sfrp2 promote cardiac progenitor cell differentiation and inhibiting proliferation. Abi3bp activates integrin-β1. Src and extracellular signal regulated kinase (ERK) activation work together to inhibit proliferation. PKCζ and Akt activation switch on cardiac genes. Sfrp2 sequesters Wnt, preventing the activation of frizzled receptors. This promotes c-Jun N-terminal kinase (JNK) activation and cardiac gene expression. Inhibition of β-catenin blocks the proliferation pathway in these cells. ECM indicates extracellular matrix; FRZ, frizzled; and TF, transcription factor. [Powerpoint File]

MicroRNAs and Cardiac Regeneration

MicroRNAs and Cardiac Regeneration

Conrad P. Hodgkinson, Martin H. Kang*, Sophie Dal-Pra*, Maria Mirotsou, Victor J. Dzau

MicroRNAs (miRNAs/miR) and reprogramming. miRNAs promote the generation of cardiomyocytes via several mechanisms. Fibroblasts (FB) can be reprogrammed into cardiomyocytes (CM) by miRNAs directly or through an intermediate inducible pluripotent stem (iPSC) state. miRNAs also promote cardiac progenitor cell (CPC) and embryonic stem cell (ESC) cardiac differentiation. miRNAs can promote or inhibit cardiomycyte proliferation. [Powerpoint File]

Use of Mesenchymal Stem Cells for Therapy of Cardiac Disease

Use of Mesenchymal Stem Cells for Therapy of Cardiac Disease

Vasileios Karantalis, Joshua M. Hare

Immunomodulatory capabilities of mesenchymal stem cells (MSCs). Schematic overview of the interactions between MSC and the immune system. Via multiple pathways, MSCs suppress proliferation of both T helper (TH) and cytotoxic T cells (Tc). In addition, differentiation to TH2 and regulatory T-cells (Treg) is triggered, resulting in an anti-inflammatory environment. Maturation of dendritic cells (DC) is inhibited via interleukin (IL)-6, blocking upregulation of CD40, CD80, and CD86, which in turn reduce T-cell activation. Monocytes are induced by MSC to differentiate preferentially toward the M2 phenotype. IL-10 produced by the M2 macrophages can boost the formation of Treg, whereas simultaneously reducing tissue migration of neutrophils. Neutrophils (polymorphonuclear granulocytes; PMN) are allowed longer life span but reactive oxygen species production is decreased. Natural Killer (NK) cell proliferation is suppressed as well as their cytotoxic activity. B-cell proliferation is inhibited and the production of antibodies is reduced. Modified from van den Akker et al.46 HGF indicates hepatocyte growth factor; IDO, indoleamine-pyrrole-2-3-dioxygenase; PGE2, prostaglandin E2; and TGF-β, transforming growth factor-β. [Powerpoint FIle]

Use of Mesenchymal Stem Cells for Therapy of Cardiac Disease

Use of Mesenchymal Stem Cells for Therapy of Cardiac Disease

Vasileios Karantalis, Joshua M. Hare

Mechanisms of action of mesenchymal stem cells (MSCs). The proposed mechanism of action of MSCs form an intertwined cycle of paracrine, autocrine, and direct effects that include vascular regeneration, myocardial protection, cardiomyocyte regeneration that ultimately lead to cardiac repair. Miro1 indicates mitochondrial Rho-GTPase. [Poweroint File]

Use of Mesenchymal Stem Cells for Therapy of Cardiac Disease

Use of Mesenchymal Stem Cells for Therapy of Cardiac Disease

Vasileios Karantalis, Joshua M. Hare

The evolution of mesenchymal stem cell (MSC) therapy for cardiac disease. MSCs will play the central role in combination therapies supporting and orchestrating different cell types. Cytokines may also be given with or pretreat the target organ before MSC transplantation. A more challenging but promising way is the genetic modification of MSCs. MPC indicates mesenchymal precursor cells. [Powerpoint File]