Cardiac Regeneration Using Isl1-positive Cardiac Progenitor Cells

2013 ◽  
pp. 185-209
Author(s):  
Yasuhiro Nakashima ◽  
Atsushi Nakano
Keyword(s):  
Progenitor Cells ◽  
Cardiac Regeneration ◽  
Cardiac Progenitor Cells

Abstract 18698: Identification of a Novel Cardiac Progenitor Population Expressing Pw1/peg3 in the Murine Heart

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Elisa Yaniz-Galende ◽  
Luigi Formicola ◽  
Nathalie Mougenot ◽  
Lise Legrand ◽  
Jiqiu Chen ◽  
...  
Keyword(s):  
Progenitor Cells ◽  
Fold Increase ◽  
Cardiac Regeneration ◽  
Cardiac Repair ◽  
Cardiac Progenitor Cells ◽  
Average Percentage ◽  
Pathological Conditions ◽  
Reporter Mice ◽  
Novel Target

The myocardium responds to injury by recruiting cardiac progenitor cells (CPCs) to the injured tissue to promote cardiac repair. Although different classes of CPCs have been identified, their contribution in physiological and pathological conditions remains unclear. PW1 gene has recently been proposed as a marker of resident adult stem and progenitor cell populations in several adult tissues. Our goal was to characterize and determine the role of PW1+ population in the heart. Here, we employ immunostaining and fluorescence-activated cell sorting (FACS) analysis in PW1-reporter mouse to perform qualitative and quantitative analyses of PW1+ population in the heart. We first found that PW1+ cells are mainly located in the epicardium and myocardial interstitium of normal hearts. The average percentage of PW1+ cells, as assessed by FACS, was 1.56±1.41%. A subset of PW1+ cells also co-express other CPC markers such as Sca-1 (52±22%) or PDGFR1α (43±14%). In contrast, a very small proportion of PW1+ cells co-express c-kit (6±5%). To investigate the contribution of PW1+ cells in pathological conditions, we then performed myocardial infarction (MI) by LAD ligation in PW1-reporter mice. We found that MI resulted in a 3-fold increase in the number of PW1+ cells in infarcted mice compared with sham-operated groups, at 1 week post-MI (1.16%±0.47% in sham versus 3.43%±0.82 in MI). This population preferentially localized in the injured myocardium and border area. PW1+ cells were isolated by FACS from the whole infarcted heart from PW1-reporter mice. In vitro differentiation assays reveal that purified PW1+ cells are multipotent and can spontaneously differentiate into smooth muscle cells, endothelial cells and cardiomyocyte-like cells. Taken together, our data identify a novel PW1+ cardiac progenitor population with the potential to undergo differentiation into multiple cardiac lineages, suggesting their involvement in cardiac repair in normal and pathological conditions. The discovery of a novel population of cardiac progenitor cells, augmented following MI and with cardiogenic potential, provides a novel target for therapeutic approaches aimed at improving cardiac regeneration.

scholarly journals Phenotypic Screen with the Human Secretome Identifies FGF16 as Inducing Proliferation of iPSC-Derived Cardiac Progenitor Cells

2019 ◽  
Vol 20 (23) ◽  
pp. 6037 ◽  
Author(s):  
Karin Jennbacken ◽  
Fredrik Wågberg ◽  
Ulla Karlsson ◽  
Jerry Eriksson ◽  
Lisa Magnusson ◽  
...  
Keyword(s):  
Progenitor Cells ◽  
Cardiac Fibroblasts ◽  
Cardiac Regeneration ◽  
Cardiac Cells ◽  
Mouse Heart ◽  
Cardiac Progenitor Cells ◽  
High Sequence Identity ◽  
Paracrine Factors ◽  
Human Cardiomyocytes ◽  
Phenotypic Screen

Paracrine factors can induce cardiac regeneration and repair post myocardial infarction by stimulating proliferation of cardiac cells and inducing the anti-fibrotic, antiapoptotic, and immunomodulatory effects of angiogenesis. Here, we screened a human secretome library, consisting of 923 growth factors, cytokines, and proteins with unknown function, in a phenotypic screen with human cardiac progenitor cells. The primary readout in the screen was proliferation measured by nuclear count. From this screen, we identified FGF1, FGF4, FGF9, FGF16, FGF18, and seven additional proteins that induce proliferation of cardiac progenitor cells. FGF9 and FGF16 belong to the same FGF subfamily, share high sequence identity, and are described to have similar receptor preferences. Interestingly, FGF16 was shown to be specific for proliferation of cardiac progenitor cells, whereas FGF9 also proliferated human cardiac fibroblasts. Biosensor analysis of receptor preferences and quantification of receptor abundances suggested that FGF16 and FGF9 bind to different FGF receptors on the cardiac progenitor cells and cardiac fibroblasts. FGF16 also proliferated naïve cardiac progenitor cells isolated from mouse heart and human cardiomyocytes derived from induced pluripotent cells. Taken together, the data suggest that FGF16 could be a suitable paracrine factor to induce cardiac regeneration and repair.

Abstract 23: p53 Mediates de novo Cardiomyocte Differentiation From c-kit Positive Cardiac Progenitor Cells

2016 ◽  
Vol 119 (suppl_1) ◽  
Author(s):  
Zhongming Chen ◽  
Wuqiang Zhu ◽  
Amritha Yellamilli ◽  
Ingrid Bender ◽  
Jop H van Berlo
Keyword(s):  
Progenitor Cells ◽  
De Novo ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Cardiac Regeneration ◽  
Cardiac Progenitor Cells ◽  
Cardiomyocyte Differentiation ◽  
P53 Expression ◽  
Lineage Differentiation

The heart is arguably the least regenerative organ. Nonetheless, cardiac progenitor cells (CPCs) can readily be isolated from the adult heart. Moreover, we recently demonstrated that c-kit+ CPCs are able to generate de novo lineages of cardiomyocytes, endothelial cells and fibroblasts, albeit at low levels. In the present study, we assess if different pathophysiological stimuli could enhance cardiomyocyte lineage differentiation by CPCs. We first established that CPCs are heterogeneous in vivo and can be classified into three main populations based on the respective gene expression profiles: uncommitted, vascular and cardiogenic CPCs. Next, we show that transverse aortic constriction (TAC) surgery increased CPC derived cardiomyocytes by 3-fold, and enhanced non-cardiomyocyte lineages as well. Interestingly, anthracycline-induced cardiomyopathy increased CPC-derived cardiomyocytes by 35-fold. Immunostaining showed that doxorubicin stimulates p53 expression within CPCs and selectively enhanced CPC-derived cardiomyocyte lineage. The selective p53 inhibitor, pifithrin α, completely blocked the doxorubicin-mediated increase in de novo cardiomyocyte formation. Administration of p53 Activator III, RITA (reactivation of p53 and induction of tumor cell apoptosis), was sufficient to induce CPC-derived cardiomyocyte differentiation. These results demonstrate that anthracyclines can increase de novo cardiomyocyte differentiation from CPCs through activation of the p53 pathway. Ultimately, these findings might lead to new therapies for cardiac regeneration by inducing cardiomyocyte differentiation by endogenous CPCs.

Abstract 51: Nucleostemin Induced by Pim-1 Kinase Is Critical to Maintain Pluripotency and Enhance Regenerative Potential of Cardiac Progenitor Cells

2012 ◽  
Vol 111 (suppl_1) ◽  
Author(s):  
Nirmala Hariharan ◽  
Anya Y Joyo ◽  
Kaitlen M Samse ◽  
Daniele Avitabile ◽  
Brandi Bailey ◽  
...  
Keyword(s):  
Progenitor Cells ◽  
Shape Control ◽  
Kinase Inhibitor ◽  
Cardiac Regeneration ◽  
Stem Cell Marker ◽  
Cardiac Progenitor Cells ◽  
Protein Levels ◽  
Regulation Of Cell Cycle ◽  
Factor C

Myocardial regeneration and repair in response to injury are governed in part by cell survival, proliferation and pluripotency. Proliferation and survival in cardiac progenitor cells (CPCs) are mediated by Pim-1, a serine threonine kinase, and nucleostemin (NS), a nucleolar stress sensor protein. The role of NS in regulating CPC pluripotency and the molecular mechanism of NS induction and action is largely unknown. The hypothesis of the study is that NS, induced by Pim-1 mediated stabilization of transcription factor c-Myc is critical to maintain CPC pluripotency and inhibits senescence. NS and c-Myc protein levels are increased in cultured CPCs overexpressing Pim-1 (3.1 and 5.5 fold, p<0.01) while knockdown of Pim-1 using sh-RNA decreases c-Myc and NS expression (-60%, -54%, p<0.05), similar to effects mediated by a Pim-1 kinase inhibitor (p<0.01), indicating that Pim-1 regulates both c-Myc and NS. c-Myc is necessary and sufficient for NS regulation, as indicated by the increase (3.1 fold, p<0.01) and decrease (-60.2%, p<0.01) in NS expression upon lentiviral mediated over-expression or knockdown of c-Myc, respectively. Regulation of NS promoter by c-Myc is evident from loss of GFP expression and fluorescence following knock down of c-Myc in CPCs isolated from transgenic mice expressing eGFP driven by the NS promoter. The role of NS in regulating CPC pluripotency is determined by silencing NS. Change in morphology (flat, round cells vs spindle shape control CPCs), decreased expression of stem cell marker c-Kit (-55%, p<0.05), up-regulation of cell cycle inhibitors p53 and p16 (4.2, 3.8 fold, p<0.01) and decreased proliferation (p<0.05) result from loss of NS in CPCs, suggestive of increased senescence and loss of pluripotency. NS-mediated regulation of CPC senescence is p53 dependent, as silencing p53 reverses CPC morphology and pluripotency lost by NS depletion. In conclusion, NS which is induced downstream of Pim-1 kinase maintains pluripotency and enhances regenerative potential in CPCs. These findings are consistent with cumulative evidence that Pim-1 induced cardiac regeneration is mediated in part by NS, providing an additional mechanistic basis for benefits of genetic engineering with Pim-1 to enhance NS expression in cardiac stem cells.

Abstract 241: Cardiac TIMP-4 Dictates cardiomyocyte contractility and differentiation of embryonic stem cells into cardiomyocytes: Road to Therapy

2014 ◽  
Vol 115 (suppl_1) ◽  
Author(s):  
Pankaj Chaturvedi ◽  
Anuradha Kalani ◽  
Anastasia Familtseva ◽  
Pradip K Kamat ◽  
Naira Metriveli ◽  
...  
Keyword(s):  
Stem Cells ◽  
Embryonic Stem Cells ◽  
Progenitor Cells ◽  
Embryonic Stem ◽  
Cardiac Regeneration ◽  
Matrix Metalloproteases ◽  
Cardiac Progenitor Cells ◽  
Cardiac Phenotype ◽  
Cardiomyocyte Contractility ◽  
Ros Scavenger

The remarkable nature of cardiomyocytes for contractility is attributed to the extracellular matrix which is maintained by the balance between MMPs (Matrix Metalloproteases) and TIMPs (Tissue Inhibitors of Matrix Metalloproteases). Any deviation from this delicate balance of MMP/TIMP is a hallmark of cardiovascular pathologies including myocardial infarction (MI). TIMP4, which is the least studied molecule, is deficient in failing hearts and mice lacking TIMP4 show poor regeneration capacity after MI. Therefore, we hypothesize that TIMP4 helps in cardiac regeneration by alleviating contractility and inducing the differentiation of cardiac progenitor cells into cardiomyocytes. To validate this hypothesis, we transfected cardiomyocytes with TIMP4 and TIMP4-siRNA and observed that there was increase in contractility in the TIMP4 transfected cardiomyocytes as compared to siRNA-TIMP4 transfected cardiomyocytes. To explain this we looked into the calcium channel genes and found increase in the expression of serca2a (sarcoplasmic reticulum calcium ATPase2a) in the TIMP4 transformed myocytes. Serca2a is tightly regulated by mir122a and we found decrease in the expression of mir122a in the TIMP4 transfected cells as compared to the TIMP4-siRNA cells. To observe the effect of TIMP4 in differentiation of cardiac progenitor cells we treated mouse embryonic stem cells with cardiac extract and cardiac extract minus TIMP4 (using TIMP4 monoclonal antibody). The cells treated with cardiac extract showed cardiac phenotype in terms of Ckit+, GATA4+ and Nkx2.5 expression. This is a novel report on the influence of TIMP4 on contractility and inducing the differentiation of stem cells to cardiomyocytes. In view of the failure of MMP9 inhibitors for cardiac therapy in clinical trials, TIMP4 provides and alternative approach, being an indigenous molecule, a natural inhibitor of MMP9 and efficient ROS scavenger.

scholarly journals Effects of Spaceflight and Simulated Microgravity on YAP1 Expression in Cardiovascular Progenitors: Implications for Cell-Based Repair

2019 ◽  
Vol 20 (11) ◽  
pp. 2742 ◽  
Author(s):  
Victor Camberos ◽  
Jonathan Baio ◽  
Leonard Bailey ◽  
Nahidh Hasaniya ◽  
Larry V. Lopez ◽  
...  
Keyword(s):  
Progenitor Cells ◽  
Simulated Microgravity ◽  
Cardiac Development ◽  
Hippo Pathway ◽  
Space Station ◽  
Cardiac Regeneration ◽  
Cardiac Progenitor Cells ◽  
Hippo Signaling ◽  
Sheep Model ◽  
The Hippo Pathway

Spaceflight alters many processes of the human body including cardiac function and cardiac progenitor cell behavior. The mechanism behind these changes remains largely unknown; however, simulated microgravity devices are making it easier for researchers to study the effects of microgravity. To study the changes that take place in cardiac progenitor cells in microgravity environments, adult cardiac progenitor cells were cultured aboard the International Space Station (ISS) as well as on a clinostat and examined for changes in Hippo signaling, a pathway known to regulate cardiac development. Cells cultured under microgravity conditions, spaceflight-induced or simulated, displayed upregulation of downstream genes involved in the Hippo pathway such as YAP1 and SOD2. YAP1 is known to play a role in cardiac regeneration which led us to investigate YAP1 expression in a sheep model of cardiovascular repair. Additionally, to mimic the effects of microgravity, drug treatment was used to induce Hippo related genes as well as a regulator of the Hippo pathway, miRNA-302a. These studies provide insight into the changes that occur in space and how the effects of these changes relate to cardiac regeneration studies.

Cardiac progenitor cells in terminally failing hearts: Immunohistological observations in human myocardium

2007 ◽  
Vol 55 (S 1) ◽  
Author(s):  
M Arnold ◽  
V Kufer ◽  
A Schütz ◽  
B Reiter ◽  
M Fittkau ◽  
...  
Keyword(s):  
Progenitor Cells ◽  
Human Myocardium ◽  
Cardiac Progenitor Cells

Breakthrough Regenerative Cardiopoietic Stem Cells and Related Technologies in the Field of Cardiovascular Medicine – From Bench to Bedside

2012 ◽  
Vol 7 (1) ◽  
pp. 14
Author(s):  
Christian Homsy ◽  
Keyword(s):  
Stem Cells ◽  
Cell Therapy ◽  
Progenitor Cells ◽  
Cardiac Disease ◽  
Cardiac Tissue ◽  
Cardiac Repair ◽  
Cardiac Diseases ◽  
Cardiac Progenitor Cells ◽  
Biotechnology Company ◽  
Cardiovascular Medicine

The scale of cardiac diseases, and in particular heart failure and acute myocardial infarction, emphasises the need for radically new approaches, such as cell therapy, to address the underlying cause of the disease, the loss of functional myocardium. Stem cell-based therapies, whether through transplanted cells or directing innate repair, may provide regenerative approaches to cardiac diseases by halting, or even reversing, the events responsible for progression of organ failure. Cardio3 BioSciences, a leading Belgian biotechnology company focused on the discovery and development of regenerative and protective therapies for the treatment of cardiac disease, was founded in this context in 2004. The company is developing a highly innovative cell therapy approach based on a platform designed to reprogramme the patient’s own stem cells into cardiac progenitor cells. The underlying rationale behind this approach is that, in order to reconstruct cardiac tissue, stem cells need to be specific to cardiac tissue. The key is therefore to provide cardiac-specific progenitor cells to the failing heart to induce cardiac repair.

scholarly journals Diabetes induces dysregulation of microRNAs associated with survival, proliferation and self-renewal in cardiac progenitor cells

Diabetologia ◽  
2021 ◽  
Author(s):  
Nima Purvis ◽  
Sweta Kumari ◽  
Dhananjie Chandrasekera ◽  
Jayanthi Bellae Papannarao ◽  
Sophie Gandhi ◽  
...  
Keyword(s):  
Progenitor Cells ◽  
Cardiac Progenitor Cells ◽  
Self Renewal
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