scholarly journals Unfathomed Nanomessages to the Heart: Translational Implications of Stem Cell-Derived, Progenitor Cell Exosomes in Cardiac Repair and Regeneration

Cells ◽  
2021 ◽  
Vol 10 (7) ◽  
pp. 1811
Author(s):  
Charan Thej ◽  
Raj Kishore
Keyword(s):  
Cardiovascular Diseases ◽  
Progenitor Cells ◽  
Cardiac Fibroblasts ◽  
Cell Communication ◽  
Cardiac Regeneration ◽  
Cell Types ◽  
Cardiac Cells ◽  
The Body ◽  
Target Cells

Exosomes formed from the endosomal membranes at the lipid microdomains of multivesicular bodies (MVBs) have become crucial structures responsible for cell communication. This paracrine communication system between a myriad of cell types is essential for maintaining homeostasis and influencing various biological functions in immune, vasculogenic, and regenerative cell types in multiple organs in the body, including, but not limited to, cardiac cells and tissues. Characteristically, exosomes are identifiable by common proteins that participate in their biogenesis; however, many different proteins, mRNA, miRNAs, and lipids, have been identified that mediate intercellular communication and elicit multiple functions in other target cells. Although our understanding of exosomes is still limited, the last decade has seen a steep surge in translational studies involving the treatment of cardiovascular diseases with cell-free exosome fractions from cardiomyocytes (CMs), cardiosphere-derived cells (CDCs), endothelial cells (ECs), mesenchymal stromal cells (MSCs), or their combinations. However, most primary cells are difficult to culture in vitro and to generate sufficient exosomes to treat cardiac ischemia or promote cardiac regeneration effectively. Pluripotent stem cells (PSCs) offer the possibility of an unlimited supply of either committed or terminally differentiated cells and their exosomes for treating cardiovascular diseases (CVDs). This review discusses the promising prospects of treating CVDs using exosomes from cardiac progenitor cells (CPCs), endothelial progenitor cells (EPCs), MSCs, and cardiac fibroblasts derived from PSCs.

Abstract 313: Twist Contributes to Cardiomyocyte Renewal and is Required for Maintenance of Adult Cardiac Function

2015 ◽  
Vol 117 (suppl_1) ◽  
Author(s):  
Yi-Li Min ◽  
Svetlana Bezprozvannaya ◽  
Drazen Šošic ◽  
Young-Jae Nam ◽  
Hesham Sadek ◽  
...  
Keyword(s):  
Cardiac Function ◽  
Cardiac Fibroblasts ◽  
Cell Lineage ◽  
Cardiac Regeneration ◽  
Cell Types ◽  
Bhlh Transcription Factor ◽  
Adult Heart ◽  
Twist 1 ◽  
Essential Contribution

Cardiomyocyte renewal occurs very slowly in adult mammals, and little is known of the genetic basis of cardiac regeneration. Twist is a highly conserved bHLH transcription factor responsible for Drosophila mesoderm formation during embryogenesis. Recent studies have shown that Twist protein is essential for muscle regeneration in adult Drosophila, but the potential role of Twist in the mammalian heart has not been explored. There are two Twist genes in vertebrates, Twist-1 and -2. We show that Twist-1 and -2 are expressed in epicardium and interstitial cells but not in differentiated cardiomyocytes in mice. To understand the potential function of Twist-dependent lineages in the adult heart, we generated inducible Twist2CreERT2; ROSA26-tdTomato reporter mice. By treating these mice with tamoxifen at 8 weeks of age, we observed progressive labeling of various cell types, such as epithelial cells, cardiac fibroblasts, and cardiomyocytes in the heart. We isolated Tomato-positive nonmyocytes from these mice and found that these cells can differentiate into cardiomyocytes and other cell types in vitro. Furthermore, cardiac-specific deletion of both Twist1 and Twist2 resulted in an age-dependent lethal cardiomyopathy. These findings reveal an essential contribution of Twist to long-term maintenance of cardiac function and support the concept of slow, lifelong renewal of cardiomyocytes from a Twist-dependent cell lineage in the adult heart.

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.

scholarly journals IL-6 loss causes ventricular dysfunction, fibrosis, reduced capillary density, and dramatically alters the cell populations of the developing and adult heart

2009 ◽  
Vol 296 (5) ◽  
pp. H1694-H1704 ◽  
Author(s):  
Indroneal Banerjee ◽  
John W. Fuseler ◽  
Arti R. Intwala ◽  
Troy A. Baudino
Keyword(s):  
Cardiac Function ◽  
Cardiac Fibroblasts ◽  
Cell Communication ◽  
Cell Types ◽  
Capillary Density ◽  
Cell Populations ◽  
Cardiac Cell ◽  
Altered Expression ◽  
Cell Cell

Interleukin-6 (IL-6) is a pleiotropic cytokine responsible for many different processes including the regulation of cell growth, apoptosis, differentiation, and survival in various cell types and organs, including the heart. Recent studies have indicated that IL-6 is a critical component in the cell-cell communication between myocytes and cardiac fibroblasts. In this study, we examined the effects of IL-6 deficiency on the cardiac cell populations, cardiac function, and interactions between the cells of the heart, specifically cardiac fibroblasts and myocytes. To examine the effects of IL-6 loss on cardiac function, we used the IL-6 −/− mouse. IL-6 deficiency caused severe cardiac dilatation, increased accumulation of interstitial collagen, and altered expression of the adhesion protein periostin. In addition, flow cytometric analyses demonstrated dramatic alterations in the cardiac cell populations of IL-6 −/− mice compared with wild-type littermates. We observed a marked increase in the cardiac fibroblast population in IL-6 −/− mice, whereas a concomitant decrease was observed in the other cardiac cell populations examined. Moreover, we observed increased cell proliferation and apoptosis in the developing IL-6 −/− heart. Additionally, we observed a significant decrease in the capillary density of IL-6 −/− hearts. To elucidate the role of IL-6 in the interactions between cardiac fibroblasts and myocytes, we performed in vitro studies and demonstrated that IL-6 deficiency attenuated the activation of the STAT3 pathway and VEGF production. Taken together, these data demonstrate that a loss of IL-6 causes cardiac dysfunction by shifting the cardiac cell populations, altering the extracellular matrix, and disrupting critical cell-cell interactions.

Exosomes and cardiovascular cell–cell communication

2018 ◽  
Vol 62 (2) ◽  
pp. 193-204 ◽  
Author(s):  
Adam J. Poe ◽  
Anne A. Knowlton
Keyword(s):  
Biological Fluids ◽  
Cell Communication ◽  
Cell Types ◽  
Cardiac Cells ◽  
The Body ◽  
Biologically Active ◽  
Surrounding Tissue ◽  
Intercellular Signaling ◽  
Cardiac Damage ◽  
Almost All

Exosomes have become an important player in intercellular signaling. These lipid microvesicles can stably transfer miRNA, protein, and other molecules between cells and circulate throughout the body. Exosomes are released by almost all cell types and are present in most if not all biological fluids. The biologically active cargo carried by exosomes can alter the phenotype of recipient cells. Exosomes increasingly are recognized as having an important role in the progression and treatment of cardiac disease states. Injured cardiac cells can release exosomes with important pathological effects on surrounding tissue, in addition to effecting other organs. But of equal interest is the possible benefit(s) conferred by exosomes released from stem cells for use in treatment and possible repair of cardiac damage.

scholarly journals Glucocorticoid Receptor β (GRβ): Beyond Its Dominant-Negative Function

2021 ◽  
Vol 22 (7) ◽  
pp. 3649
Author(s):  
Patricia Ramos-Ramírez ◽  
Omar Tliba
Keyword(s):  
Current Knowledge ◽  
Inflammatory Diseases ◽  
Cell Communication ◽  
Cell Types ◽  
The Body ◽  
Dominant Negative ◽  
Negative Effects ◽  
Independent Manner ◽  
Distinct Cell ◽  
Induced Apoptosis

Glucocorticoids (GCs) act via the GC receptor (GR), a receptor ubiquitously expressed in the body where it drives a broad spectrum of responses within distinct cell types and tissues, which vary in strength and specificity. The variability of GR-mediated cell responses is further extended by the existence of GR isoforms, such as GRα and GRβ, generated through alternative splicing mechanisms. While GRα is the classic receptor responsible for GC actions, GRβ has been implicated in the impairment of GRα-mediated activities. Interestingly, in contrast to the popular belief that GRβ actions are restricted to its dominant-negative effects on GRα-mediated responses, GRβ has been shown to have intrinsic activities and “directly” regulates a plethora of genes related to inflammatory process, cell communication, migration, and malignancy, each in a GRα-independent manner. Furthermore, GRβ has been associated with increased cell migration, growth, and reduced sensitivity to GC-induced apoptosis. We will summarize the current knowledge of GRβ-mediated responses, with a focus on the GRα-independent/intrinsic effects of GRβ and the associated non-canonical signaling pathways. Where appropriate, potential links to airway inflammatory diseases will be highlighted.

Clock gene-independent daily regulation of haemoglobin oxidation in red blood cells

2021 ◽  
Author(s):  
Andrew D. Beale ◽  
Priya Crosby ◽  
Utham K. Valekunja ◽  
Rachel S. Edgar ◽  
Johanna E. Chesham ◽  
...  
Keyword(s):  
Circadian Rhythms ◽  
Red Blood Cells ◽  
Blood Cells ◽  
Human Subjects ◽  
Developmental Regulation ◽  
Physiological Role ◽  
Cell Types ◽  
The Body

AbstractCellular circadian rhythms confer daily temporal organisation upon behaviour and physiology that is fundamental to human health and disease. Rhythms are present in red blood cells (RBCs), the most abundant cell type in the body. Being naturally anucleate, RBC circadian rhythms share key elements of post-translational, but not transcriptional, regulation with other cell types. The physiological function and developmental regulation of RBC circadian rhythms is poorly understood, however, partly due to the small number of appropriate techniques available. Here, we extend the RBC circadian toolkit with a novel biochemical assay for haemoglobin oxidation status, termed “Bloody Blotting”. Our approach relies on a redox-sensitive covalent haem-haemoglobin linkage that forms during cell lysis. Formation of this linkage exhibits daily rhythms in vitro, which are unaffected by mutations that affect the timing of circadian rhythms in nucleated cells. In vivo, haemoglobin oxidation rhythms demonstrate daily variation in the oxygen-carrying and nitrite reductase capacity of the blood, and are seen in human subjects under controlled laboratory conditions as well as in freely-behaving humans. These results extend our molecular understanding of RBC circadian rhythms and suggest they serve an important physiological role in gas transport.

Abstract 129: Embryonic Stem Cell Derived Exosomes Revive Endogenous Repair Mechanisms In Failing Heart

2014 ◽  
Vol 115 (suppl_1) ◽  
Author(s):  
Mohsin Khan ◽  
Suresh K Verma ◽  
Alexander R Mackie ◽  
Erin Vaughan ◽  
Srikanth Garikipati ◽  
...  
Keyword(s):  
Stem Cells ◽  
Therapeutic Potential ◽  
Embryonic Stem ◽  
Cardiac Regeneration ◽  
Great Promise ◽  
Target Cells ◽  
Free System ◽  
Teratoma Formation

Rationale: Embryonic stem cells (ESCs) hold great promise for cardiac regeneration but are susceptible to ethical concerns, lack of autologous donors and teratoma formation. Recently, it has been observed that beneficial effects of stem cells are mediated by exosomes secreted out under various physiological conditions. ESCs have the ability to produce exosomes however their effect in the context of the heart is unknown. Objective: Determine the effect of ESC derived exosomes for cardiac repair and modulation of CPCs functions in the heart following myocardial infarction. Methods and Results: Exosomes were isolated from murine ESCs (mES Ex) or embryonic fibroblasts (MEFs) by ultracentrifugation and verified by Flotillin-1 immunoblot analysis. Induction of pluripotent markers, survival and in vitro tube formation was enhanced in target cells receiving ESC exosomes indicating therapeutic potential of mES Ex. mES Ex administration resulted in enhanced neovascularization, cardiomyocyte survival and reduced fibrosis post infarction consistent with resurgence of cardiac proliferative response. Importantly, mES Ex mediated considerable enhancement of cardiac progenitor cell (CPC) survival, proliferation and cardiac commitment concurrent with increased c-kit+ CPCs in vivo 4 weeks after mES Ex transfer. miRNA Array analysis of ESC and MEF exosomes revealed significantly high expression of miR290-295 cluster in the ESC exosomes compared to MEF exosomes. The underlying beneficial effect of mES Ex was tied to delivery of ESC miR-294 to the heart and in particular CPCs thereby promoting CPC survival and proliferation as analyzed by FACS based cell death analysis and CyQuant assay respectively. Interestingly, enhanced G1/S transition was observed in CPCs treated with miR-294 in conjunction with significant reduction of G1 phase. Conclusion: In conclusion, mES Ex provide a novel cell free system for cardiac regeneration with the ability to modulate both cardiomyocyte and CPC based repair programs in the heart thereby avoiding the risk of teratoma formation associated with ESCs.

Abstract 255: A Fibroblast Population Shares A Developmental Origin With Cardiovascular Lineages

2014 ◽  
Vol 115 (suppl_1) ◽  
Author(s):  
Sara Ranjbarvaziri ◽  
Shah Ali ◽  
Mahmood Talkhabi ◽  
Peng Zhao ◽  
Young-Jae Nam ◽  
...  
Keyword(s):  
Heart Development ◽  
Cardiac Fibroblasts ◽  
Immunohistochemical Analysis ◽  
Cell Types ◽  
Mouse Heart ◽  
Developmental Potential ◽  
Reporter Mice ◽  
Significant Difference ◽  
Definition Of

Rationale: The traditional definition of “cardiovascular” lineages describes the eponymous cell types - cardiomyoctes, endothelial cells, and smooth muscle cells - that arise from a common mesodermal progenitor cell during heart development. Fibroblasts are an abundant mesenchymal population in the mammalian heart which may have multiple, discrete developmental origins. Mesp1 represents the earliest marker of cardiovascular progenitors, contributing to the majority of cardiac lineages. To date no link between Mesp1 and fibroblast generation has been reported. Objective: We hypothesized progenitor cells expressing Mesp1 can also give rise to cardiac fibroblasts during heart development. Methods and Results: We generated Mesp1cre/+;R26RmTmG reporter mice where Cre-mediated recombination results in GFP activation in all Mesp1 expressing cells and their progeny. To explore their developmental potential, we isolated GFP+ cells from E7.5 Mesp1cre/+;R26RmTmG mouse. In vitro culture and transplantation studies into SCID mouse kidney capsule as wells as chick embryos showed fibroblastic adoption. Results showed that at E9.5 Mesp1+ and Mesp1- progenitors contributed to the proepicardium organ and later at E11.5 they formed epicardium. Analysis of adult hearts demonstrated that the majority of cardiac fibroblasts are derived from Mesp1 expressing cells. Immunohistochemical analysis of heart sections demonstrated expression of fibroblast markers (including DDR2, PDGFRα and Col1) in cells derived from both Mesp1+ and Mesp1- progenitors. Additionally, we investigated whether the two distinct fibroblast populations have different potency towards reprogramming to cardiomyocytes. Results showed no significant difference between Mesp1 and non-Mesp1 isolated fibroblasts to convert to cardiomyocyte fate. Conclusions: Our data demonstrates that cardiovascular progenitors expressing Mesp1 contribute to the proepicardium. These cells, as cardiovascular progenitors, also give rise to the highest portion of cardiac fibroblasts in the mouse heart.

scholarly journals Extracellular Vesicles: An Emerging Mechanism Governing the Secretion and Biological Roles of Tenascin-C

2021 ◽  
Vol 12 ◽  
Author(s):  
Lucas Albacete-Albacete ◽  
Miguel Sánchez-Álvarez ◽  
Miguel Angel del Pozo
Keyword(s):  
Extracellular Vesicles ◽  
Molecular Mechanisms ◽  
Cell Communication ◽  
Cell Types ◽  
Target Cells ◽  
Tenascin C ◽  
Signalling Molecules ◽  
Inflammatory Processes ◽  
Bona Fide ◽  
Cellular Components

ECM composition and architecture are tightly regulated for tissue homeostasis. Different disorders have been associated to alterations in the levels of proteins such as collagens, fibronectin (FN) or tenascin-C (TnC). TnC emerges as a key regulator of multiple inflammatory processes, both during physiological tissue repair as well as pathological conditions ranging from tumor progression to cardiovascular disease. Importantly, our current understanding as to how TnC and other non-collagen ECM components are secreted has remained elusive. Extracellular vesicles (EVs) are small membrane-bound particles released to the extracellular space by most cell types, playing a key role in cell-cell communication. A broad range of cellular components can be transported by EVs (e.g. nucleic acids, lipids, signalling molecules and proteins). These cargoes can be transferred to target cells, potentially modulating their function. Recently, several extracellular matrix (ECM) proteins have been characterized as bona fide EV cargoes, exosomal secretion being particularly critical for TnC. EV-dependent ECM secretion might underpin diseases where ECM integrity is altered, establishing novel concepts in the field such as ECM nucleation over long distances, and highlighting novel opportunities for diagnostics and therapeutic intervention. Here, we review recent findings and standing questions on the molecular mechanisms governing EV–dependent ECM secretion and its potential relevance for disease, with a focus on TnC.

scholarly journals Modulating cell state to enhance suspension expansion of human pluripotent stem cells

2018 ◽  
Vol 115 (25) ◽  
pp. 6369-6374 ◽  
Author(s):  
Yonatan Y. Lipsitz ◽  
Curtis Woodford ◽  
Ting Yin ◽  
Jacob H. Hanna ◽  
Peter W. Zandstra
Keyword(s):  
Stem Cells ◽  
Pluripotent Stem Cells ◽  
Large Scale ◽  
Cell Types ◽  
Human Pluripotent Stem Cells ◽  
The Body ◽  
Altered Expression ◽  
Pancreatic Progenitors ◽  
Erk Inhibition

The development of cell-based therapies to replace missing or damaged tissues within the body or generate cells with a unique biological activity requires a reliable and accessible source of cells. Human pluripotent stem cells (hPSC) have emerged as a strong candidate cell source capable of extended propagation in vitro and differentiation to clinically relevant cell types. However, the application of hPSC in cell-based therapies requires overcoming yield limitations in large-scale hPSC manufacturing. We explored methods to convert hPSC to alternative states of pluripotency with advantageous bioprocessing properties, identifying a suspension-based small-molecule and cytokine combination that supports increased single-cell survival efficiency, faster growth rates, higher densities, and greater expansion than control hPSC cultures. ERK inhibition was found to be essential for conversion to this altered state, but once converted, ERK inhibition led to a loss of pluripotent phenotype in suspension. The resulting suspension medium formulation enabled hPSC suspension yields 5.7 ± 0.2-fold greater than conventional hPSC in 6 d, for at least five passages. Treated cells remained pluripotent, karyotypically normal, and capable of differentiating into all germ layers. Treated cells could also be integrated into directed differentiated strategies as demonstrated by the generation of pancreatic progenitors (NKX6.1+/PDX1+ cells). Enhanced suspension-yield hPSC displayed higher oxidative metabolism and altered expression of adhesion-related genes. The enhanced bioprocess properties of this alternative pluripotent state provide a strategy to overcome cell manufacturing limitations of hPSC.

Sign in / Sign up

Export Citation Format

Share Document