Posts Tagged: regeneration

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]

“String Theory” of c-kitpos Cardiac Cells: A New Paradigm Regarding the Nature of These Cells That May Reconcile Apparently Discrepant Results

“String Theory” of c-kitpos Cardiac Cells: A New Paradigm Regarding the Nature of These Cells That May Reconcile Apparently Discrepant Results

Matthew C.L. Keith, Roberto Bolli

Proposed origin of c-kitpos cells in the adult heart. The figure illustrates the concept that, in the adult heart, c-kitpos cells are intermediates derived from c-kitneg epicardial progenitors that undergo epithelial-to-mesenchymal transition (EMT). (EMT is known to be associated with expression of c-kit.) These c-kitpos intermediates have a mesenchymal phenotype and give rise to c-kitneg epicardium-derived cells (EPDCs) with differentiation potential limited to noncardiomyocytic lineages. A, Wilm’s tumor protein (WT)-1+/T-box transcription factor (Tbx) 18+ epicardial progenitors contribute predominantly to smooth muscle and cardiac adventitial fibroblasts, with minimal endothelial cell formation. B, Sema3D+/Scx+ epicardial progenitors (distinct from WT-1+/Tbx18+ cells) form vascular endothelium and cardiac fibroblasts and contribute minimally to smooth muscle cells. Both of these epicardium-derived c-kitpos intermediates express CD105 and possess a mesenchymal phenotype with canonical mesenchymal stromal/stem cell (MSC) markers; neither of these two populations has shown any significant ability to form myocytes. The expression of c-kit in these epicardium-derived intermediates is postulated to be high relative to that of c-kitpos intermediates from the FHF (shown in Figure 1), which have bipotent cardiomyocyte and smooth muscle differentiation capacity. This differential c-kit expression among cardiac progenitors is currently a conjecture and has not been demonstrated experimentally; nevertheless, it is inferred from the results of the van Berlo study, which did not detect significant myogenesis from first heart field c-kitpos progenitors but detected robust evidence of a c-kitpos progenitor of fibroblasts, smooth muscle cells, and endothelial cells (all of which are of epicardial origin), and from the proposed insensitivity of the van Berlo model to low levels of c-kit expression, which could theoretically result in underestimation of low expressers of c-kit. Shown below the figure is the relative contribution of mesenchymally transitioned EPDCs to cardiac lineages of the adult heart; this pattern is consistent with studies of adult c-kitpos cells, which have shown preferential adventitial and vasculogenic differentiation and a paucity of direct cardiomyogenic potential. [Powerpoint File]

Developmental and Regenerative Biology of Multipotent Cardiovascular Progenitor Cells

Developmental and Regenerative Biology of Multipotent Cardiovascular Progenitor Cells

Anthony C. Sturzu, Sean M. Wu

Proposed cellular hierarchy of cardiac progenitor cells and their lineage diversification. Precursors for heart-forming cells in the vertebrate mesoderm transition from expressing brachyury T to Mesp1 when they enter the precardiac mesoderm stage of development. As these early cardiac mesodermal cells contribute to the developing heart, their transcriptional program determines their further lineage specification. Within the second heart field, Isl1, together with Nkx2.5 and Flk1, defines multipotent Isl1+ cardiovascular progenitor cells that can give rise to myocardial, conduction system, smooth muscle, and endothelial lineages. A subset of precursors derived from Isl1+ progenitors may function as more restricted bipotent progenitors, displaying myocardial and smooth muscle potential or endothelial and smooth muscle potential. The developmental potential of the first heart field progenitors is largely uncharacterized. Epicardial progenitor cells are marked by Wt1 and/or Tbx18. These cells have been shown to give rise to cardiomyocytes, smooth muscle, endothelial cells, and fibroblasts in the heart. CD31 (PECAM 1) indicates platelet/endothelial cell adhesion molecule; cTnT, cardiac troponin T; DDR2, discoidin domain receptor 2; FHF, first heart field; HCN4, potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 4; SHF, second heart field; sm-actin, smooth muscle actin; smMHC, smooth muscle myosin heavy chain. (Illustration Credit: Cosmocyte/Ben Smith). [Powerpoint File]

Mesenchymal Stem Cells: Biology, Pathophysiology, Translational Findings, and Therapeutic Implications for Cardiac Disease

Mesenchymal Stem Cells: Biology, Pathophysiology, Translational Findings, and Therapeutic Implications for Cardiac Disease

Adam R. Williams, Joshua M. Hare

MSC interactions with immune cells. MSCs are immunoprivileged cells that inhibit both innate (neutrophils, dendritic cells, natural killer cells) and adaptive (T cells and B cells) immune cells. Illustration credit: Cosmocyte/Ben Smith. INF-γ indicates interferon-γ; TNF, tumor necrosis factor. (Illustration credit: Cosmocyte/Ben Smith.) [Powerpoint File]

Empowering Adult Stem Cells for Myocardial Regeneration

Empowering Adult Stem Cells for Myocardial Regeneration

Sadia Mohsin, Sailay Siddiqi, Brett Collins, Mark A. Sussman

Adult cardiac stem cell requires empowerment. Schematic representation of enhanced cardiac stem cells (CPCs) and their potentiation for repair to damaged myocardium relative to normal CPCs. [Powerpoint File]