scholarly journals PDGFRα signaling in cardiac fibroblasts modulates quiescence, metabolism and self-renewal, and promotes anatomical and functional repair

2017 ◽  
Author(s):  
Naisana S. Asli ◽  
Munira Xaymardan ◽  
Ralph Patrick ◽  
Nona Farbehi ◽  
James Cornwell ◽  
...  
Keyword(s):  
Therapeutic Potential ◽  
Cardiac Fibroblasts ◽  
Cardiac Injury ◽  
Cell Types ◽  
Cardiac Fibroblast ◽  
Perivascular Spaces ◽  
Paracrine Signaling ◽  
Systemic Delivery ◽  
Heart Repair ◽  
Injury And Repair

SUMMARYThe interstitial and perivascular spaces of the mammalian heart contain a highly interactive tissue community essential for cardiac homeostasis, repair and regeneration. Mesenchymal cells (fibroblasts) are one of the most abundant cell types, playing key roles as sentinels, tissue architects, paracrine signaling hubs and lineage precursors, and are linked to heart disease through their roles in inflammation and fibrosis. Platelet-derived growth factors (PDGFs) are secreted by several cell types involved in cardiac injury and repair, and are recognized mitogens for cardiac fibroblasts and mesenchymal stem cells. However, their roles are complex and investigations of their impact on heart repair have produced contrasting outcomes, leaving therapeutic potential uncertain. Here, we use new approaches and tools, including single cell RNA sequencing, to explore cardiac fibroblast heterogeneity and how PDGF receptor α (PDGFRα) signaling impacts fibroblasts during heart repair. Short-term systemic delivery of PDGF-AB to mice from the time of myocardial infarction (MI) led to enhanced anatomical and functional recovery. Underpinning these benefits was a priming effect, in which PDGF-AB accelerated exit of fibroblasts from quiescence and induced a higher translational biosynthetic capacity in both fibroblasts and macrophages without triggering fibrosis. Our study highlights the significant biosynthetic heterogeneity and plasticity in cardiac fibroblast populations, and suggests a rationale for a novel therapeutic approach to cardiac injury involving controlled stimulation of fibroblast activation.

scholarly journals Profiling proliferative cells and their progeny in damaged murine hearts

2018 ◽  
Vol 115 (52) ◽  
pp. E12245-E12254 ◽  
Author(s):  
Kai Kretzschmar ◽  
Yorick Post ◽  
Marie Bannier-Hélaouët ◽  
Andrea Mattiotti ◽  
Jarno Drost ◽  
...  
Keyword(s):  
Stem Cell ◽  
Cell Function ◽  
Cardiac Fibroblasts ◽  
Cardiac Injury ◽  
Cardiac Regeneration ◽  
Cell Types ◽  
Postnatal Growth ◽  
Lineage Tracing ◽  
Genetic Lineage ◽  
Proliferating Cells

The significance of cardiac stem cell (CSC) populations for cardiac regeneration remains disputed. Here, we apply the most direct definition of stem cell function (the ability to replace lost tissue through cell division) to interrogate the existence of CSCs. By single-cell mRNA sequencing and genetic lineage tracing using two Ki67 knockin mouse models, we map all proliferating cells and their progeny in homoeostatic and regenerating murine hearts. Cycling cardiomyocytes were only robustly observed in the early postnatal growth phase, while cycling cells in homoeostatic and damaged adult myocardium represented various noncardiomyocyte cell types. Proliferative postdamage fibroblasts expressing follistatin-like protein 1 (FSTL1) closely resemble neonatal cardiac fibroblasts and form the fibrotic scar. Genetic deletion of Fstl1 in cardiac fibroblasts results in postdamage cardiac rupture. We find no evidence for the existence of a quiescent CSC population, for transdifferentiation of other cell types toward cardiomyocytes, or for proliferation of significant numbers of cardiomyocytes in response to cardiac injury.

scholarly journals Single-cell expression profiling reveals dynamic flux of cardiac stromal, vascular and immune cells in health and injury

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Nona Farbehi ◽  
Ralph Patrick ◽  
Aude Dorison ◽  
Munira Xaymardan ◽  
Vaibhao Janbandhu ◽  
...  
Keyword(s):  
Single Cell ◽  
Immune Cells ◽  
Interstitial Cell ◽  
Single Cells ◽  
Cardiac Injury ◽  
Cell Types ◽  
Cell Lineages ◽  
Heart Repair ◽  
Cell Expression ◽  
Cell Community

Besides cardiomyocytes (CM), the heart contains numerous interstitial cell types which play key roles in heart repair, regeneration and disease, including fibroblast, vascular and immune cells. However, a comprehensive understanding of this interactive cell community is lacking. We performed single-cell RNA-sequencing of the total non-CM fraction and enriched (Pdgfra-GFP+) fibroblast lineage cells from murine hearts at days 3 and 7 post-sham or myocardial infarction (MI) surgery. Clustering of >30,000 single cells identified >30 populations representing nine cell lineages, including a previously undescribed fibroblast lineage trajectory present in both sham and MI hearts leading to a uniquely activated cell state defined in part by a strong anti-WNT transcriptome signature. We also uncovered novel myofibroblast subtypes expressing either pro-fibrotic or anti-fibrotic signatures. Our data highlight non-linear dynamics in myeloid and fibroblast lineages after cardiac injury, and provide an entry point for deeper analysis of cardiac homeostasis, inflammation, fibrosis, repair and regeneration.

Abstract 250: Elucidating the Role of Platelet Derived Growth Factor Receptor Alpha Signaling in Cardiac Fibroblasts

2015 ◽  
Vol 117 (suppl_1) ◽  
Author(s):  
Malina J Ivey ◽  
Michelle Tallquist
Keyword(s):  
Preliminary Data ◽  
Time Course ◽  
Cardiac Fibrosis ◽  
Cardiac Fibroblasts ◽  
Growth Factor Receptor ◽  
Cell Types ◽  
Cardiac Fibroblast ◽  
Proliferating Cells ◽  
Time Course Experiment

Cardiac fibrosis is a major component of heart disease and is a hallmark of decreased cardiac function. Currently, there are no treatments that attenuate fibrosis directly. This major hurdle can be overcome by targeting the resident fibroblast. Preliminary data demonstrates that loss of PDGFRα expression in the adult cardiac fibroblast lineage results in loss of over half of resident fibroblasts. A time course experiment revealed that in as little as 4 days after PDGFRα gene deletion fibroblast loss can observed. Based on the basal level of fibroblast proliferation (0.8%+/-0.9, i.e. 4 of 398 cells), we hypothesize that PDGFRα signaling is essential for fibroblast maintenance and that fibroblasts undergo rapid turnover. We have begun to elucidate which downstream signals of PDGFRα are involved the different roles of the fibroblast. Using a PDGFRα-dependent-PI3K-deficient mouse model, preliminary data indicates that PDGFRα-dependent PI3K signaling is involved in this cell survival response. Future studies will investigate cardiac fibroblast maintenance signals by determining which cell types secrete PDGF ligands. We will also investigate the role of PDGFRα signaling after myocardial infarction. Our lab has genetic tools that enable us to follow fibroblasts after injury, and we have determined both the number of proliferating fibroblasts at different time points, as well as the fraction of fibroblasts that make up the total population of proliferating cells after LAD ligation. Our preliminary data in control hearts shows that fibroblasts reach their peak of proliferation within a week after infarction, although they remain one of the most proliferative cell types as long as three weeks after induction. Our studies will illuminate the role of the fibroblast in tissue homeostasis and after infarction and identify how these cells contribute to overall cardiovascular function and delineate the fine balance between the essential and detrimental functions of the fibroblast.

Abstract 318: Identification of Novel Cardiac Fibroblast Enriched Genes

2014 ◽  
Vol 115 (suppl_1) ◽  
Author(s):  
Jessica M Swonger ◽  
Michelle D Tallquist
Keyword(s):  
Differentially Expressed Genes ◽  
Heart Function ◽  
Cardiac Fibroblasts ◽  
Cardiac Injury ◽  
The United States ◽  
Cardiac Fibroblast ◽  
Differentially Expressed ◽  
Fibroblast Activation ◽  
Helix Loop Helix ◽  
Future Work

The leading cause of death in the United States is heart disease. While current therapies have reduced mortality, patients surviving the initial stages of cardiac injury are left with long-term disruption of heart function including fibrosis. Pathological fibrosis in the heart is caused by excess proliferation and deposition of extracellular matrix primarily by cardiac fibroblasts (CFs). One factor required for cardiac fibroblast formation is the basic helix-loop-helix transcription factor, TCF21 (epicardin/Pod1/capsulin). Previous studies from our lab have shown that Tcf21 null embryos lack CFs. Our current work focuses on identifying genes downstream of TCF21. Deep-sequencing identified over one hundred differentially expressed genes when comparing embryonic hearts from Tcf21 nulls to wild types. We have verified a subset of these differentially expressed genes by qPCR and have demonstrated that these genes are also expressed in cultured primary cardiac fibroblasts. Future work will focus on determining the function of these genes during fibroblast activation and determine which of these genes are directly regulated by TCF21. The elucidation of cardiac fibroblast specific genes and their function will provide much needed information for identification of therapeutic targets aimed at cardiac fibroblast activation.

scholarly journals Transplantation of Human Pluripotent Stem Cell-Derived Cardiomyocytes for Cardiac Regenerative Therapy

2021 ◽  
Vol 8 ◽  
Author(s):  
Sophia E. Silver ◽  
Ryan W. Barrs ◽  
Ying Mei
Keyword(s):  
Stem Cells ◽  
Pluripotent Stem Cells ◽  
Cardiac Tissue ◽  
Therapeutic Potential ◽  
Cardiac Injury ◽  
Human Cardiomyocytes ◽  
Heart Repair ◽  
Recent Developments ◽  
Successful Transplantation ◽  
Induced Pluripotent

Cardiovascular disease is the leading cause of death worldwide and bears an immense economic burden. Late-stage heart failure often requires total heart transplantation; however, due to donor shortages and lifelong immunosuppression, alternative cardiac regenerative therapies are in high demand. Human pluripotent stem cells (hPSCs), including human embryonic and induced pluripotent stem cells, have emerged as a viable source of human cardiomyocytes for transplantation. Recent developments in several mammalian models of cardiac injury have provided strong evidence of the therapeutic potential of hPSC-derived cardiomyocytes (hPSC-CM), showing their ability to electromechanically integrate with host cardiac tissue and promote functional recovery. In this review, we will discuss recent developments in hPSC-CM differentiation and transplantation strategies for delivery to the heart. We will highlight the mechanisms through which hPSC-CMs contribute to heart repair, review major challenges in successful transplantation of hPSC-CMs, and present solutions that are being explored to address these limitations. We end with a discussion of the clinical use of hPSC-CMs, including hurdles to clinical translation, current clinical trials, and future perspectives on hPSC-CM transplantation.

Abstract 374: Cardiac Fibroblasts are Essential During Pathological Stress

2015 ◽  
Vol 117 (suppl_1) ◽  
Author(s):  
Jill T Kuwabara
Keyword(s):  
Structural Integrity ◽  
Heart Function ◽  
Cardiac Fibroblasts ◽  
Pressure Overload ◽  
Cell Types ◽  
Capillary Density ◽  
Cardiac Fibroblast ◽  
Normal Heart ◽  
Specific Level ◽  
Adverse Remodeling

Cardiac fibroblasts reportedly play a role in normal heart function and are responsible for adverse remodeling after heart injury. Although fibroblast activities can be detrimental during disease, a basal level of cardiac fibroblast activity is required to maintain structural integrity and prevent rupture. We use transgenic mouse models to demonstrate that reduced fibroblasts numbers have serious consequences during pathological stress. At baseline, we observe a dramatic loss of the cardiac fibroblast lineage, which results in vasculature alterations, such as capillary dilation and decreased capillary density. Baseline changes in basement membrane (laminin) and cardiomyocyte structure have also been identified in fibroblast deficient hearts. These phenotypic changes become exacerbated after surgery indicating that fibroblasts are necessary for crosstalk between other cell types in the heart. In addition, we predict that the loss of fibroblasts will cause enhanced deterioration in cardiac function after injury due to reduced structural integrity of the heart. We will use transverse aortic constriction (TAC) as a pressure-overload model. After 5 weeks of TAC, we observe a ~50% (Baseline 71.99±6.06, TAC5wks 22.09±1.89) decrease in ejection fraction in fibroblast deficient hearts compared to a ~16% (Baseline 76.21±7.08, TAC5wks 59.59) decrease in control hearts. Our data suggest that a specific level of cardiac fibroblast activity is required to maintain normal heart function. Our goal is to identify both deleterious and beneficial roles of fibroblasts in the response of the heart to the types of pathological stress commonly encountered in patients.

Abstract 310: Role of Cardiac Fibroblast in Cardioprotective Effects of Prior Transient ACE Inhibition

2013 ◽  
Vol 113 (suppl_1) ◽  
Author(s):  
Taben M Hale ◽  
Lauren A Biwer ◽  
Karen M D’Souza
Keyword(s):  
Gene Expression ◽  
Cellular Proliferation ◽  
Cardiac Fibroblasts ◽  
Cardiac Injury ◽  
Ace Inhibition ◽  
Cardiac Fibroblast ◽  
Heart Weight ◽  
Nitric Oxide Synthase Inhibitor

Prior treatment with the ACE inhibitor enalapril followed by washout protects against nitric oxide synthase inhibitor (L-NAME) induced fibrosis, cellular proliferation, and cardiac dysfunction. The present study investigated i) whether in vivo L-NAME administration induces a change in cardiac fibroblast phenotype that persists in vitro, ii) whether prior ACE inhibition protects against L-NAME induced changes in cardiac fibroblasts. SHR were divided into 3 groups: Control, L-NAME (C+L: 7d), enalapril+L-NAME (E+L: 14d enalapril + 14d washout + 7d L-NAME). MAP was measured by radiotelemetry (n=5-9), injury assessed by histology (n=6-10), and heart weight to body weight (HW/BW) was determined after 0 or 7 days of L-NAME in C+L and E+L (n=6-10). In separate rats cardiac fibroblasts were isolated after 7 days of L-NAME (C+L, E+L) or placebo (Con) and cultured to passage 1 (n=10-12). Gene expression was measured by quantitative real-time PCR. L-NAME increased MAP in C+L (22±4.1%) and E+L (21±3.6%) rats. Prior enalapril induced a persistent 13% reduction in HW/BW. L-NAME increased heart mass in E+L (7%) but not C+L; however, HW/BW remained 8% lower than C+L at sacrifice. L-NAME induced infarct in 70% of C+L and 40% of E+L hearts. Cardiac fibroblasts demonstrated a significant increase in proliferation rate in C+L, but not E+L, relative to control (C+L: 1.75-fold vs. con; E+L 1.09-fold vs. con). Fibroblasts from C+L hearts tended to have increased Collagen I and III gene expression. Despite hypertension, cardiac injury, and increased HW/BW; fibroblasts isolated from E+L proliferated at the same rate as those from control. In contrast, those isolated from C+L were hyperproliferative with a tendency toward increased capacity for collagen production. It may be that the fibroblast phenotype from E+L hearts would protect against infarct expansion and account, in part, for the previously reported cardioprotection in these rats.

scholarly journals Extracellular Vesicle-Based Therapeutics for Heart Repair

Nanomaterials ◽  
2021 ◽  
Vol 11 (3) ◽  
pp. 570
Author(s):  
Laura Saludas ◽  
Cláudia C. Oliveira ◽  
Carmen Roncal ◽  
Adrián Ruiz-Villalba ◽  
Felipe Prósper ◽  
...  
Keyword(s):  
Drug Delivery ◽  
Therapeutic Potential ◽  
Therapeutic Option ◽  
Cell Communication ◽  
Membrane Vesicles ◽  
Cell Types ◽  
Extracellular Vesicle ◽  
Cardiac Damage ◽  
Heterogeneous Membrane ◽  
Heart Repair

Extracellular vesicles (EVs) are constituted by a group of heterogeneous membrane vesicles secreted by most cell types that play a crucial role in cell–cell communication. In recent years, EVs have been postulated as a relevant novel therapeutic option for cardiovascular diseases, including myocardial infarction (MI), partially outperforming cell therapy. EVs may present several desirable features, such as no tumorigenicity, low immunogenic potential, high stability, and fine cardiac reparative efficacy. Furthermore, the natural origin of EVs makes them exceptional vehicles for drug delivery. EVs may overcome many of the limitations associated with current drug delivery systems (DDS), as they can travel long distances in body fluids, cross biological barriers, and deliver their cargo to recipient cells, among others. Here, we provide an overview of the most recent discoveries regarding the therapeutic potential of EVs for addressing cardiac damage after MI. In addition, we review the use of bioengineered EVs for targeted cardiac delivery and present some recent advances for exploiting EVs as DDS. Finally, we also discuss some of the most crucial aspects that should be addressed before a widespread translation to the clinical arena.

Regulatory immune cells in kidney disease

2008 ◽  
Vol 295 (2) ◽  
pp. F335-F342 ◽  
Author(s):  
V. W. S. Lee ◽  
Y. M. Wang ◽  
Y. P. Wang ◽  
D. Zheng ◽  
T. Polhill ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Renal Disease ◽  
Immune Cells ◽  
Animal Studies ◽  
Therapeutic Potential ◽  
Tissue Injury ◽  
Cell Types ◽  
Regulatory T Lymphocytes ◽  
Injury And Repair ◽  
Exciting Possibility

Lymphocytes and macrophages act as effector immune cells in the initiation and progression of renal injury. Recent data have shown that subpopulations of these immune cells (regulatory T lymphocytes and alternately-activated or regulatory macrophages) are potent modulators of tissue injury and repair in renal disease. Recent animal studies examining the therapeutic effect of these cells raise the exciting possibility that strategies targeting these cell types may be effective in treating and preventing kidney disease in humans. This review will describe their biological role in experimental kidney disease and therapeutic potential in clinical nephrology.

scholarly journals Cardiac fibroblast mechanoresponse guides anisotropic organization of hiPSC-derived cardiomyocytes in vitro

2021 ◽  
Author(s):  
Dylan Mostert ◽  
Leda Klouda ◽  
Mark C. van Turnhout ◽  
Nicholas A. Kurniawan ◽  
Carlijn V.C Bouten
Keyword(s):  
Cardiac Fibroblasts ◽  
Mechanical Strain ◽  
Cardiac Injury ◽  
Cyclic Strain ◽  
Cell Types ◽  
Tissue Organization ◽  
A Cell ◽  
Human Cardiac Fibroblasts ◽  
And Function

ABSTRACTThe human myocardium is a mechanically active tissue typified by the anisotropic organization of cells and extracellular matrix (ECM). Upon injury, the composition of the myocardium changes, resulting in disruption of tissue organization and loss of coordinated contraction. Understanding how anisotropic organization in the adult myocardium is shaped and disrupted by environmental cues is thus critical, not only for unravelling the processes taking place during disease progression, but also for developing regenerative strategies to recover tissue function. Here, we decoupled in vitro the two major physical cues that are inherent in the myocardium: structural ECM and mechanical strain. We show that patterned ECM proteins control the orientation of the two main cell types in the myocardium: human cardiac fibroblasts (cFBs) and cardiomyocytes (hiPSC-CMs), despite their different mechanosensing machinery. Uniaxial cyclic strain, mimicking the local anisotropic deformation of the myocardium, did not affect hiPSC-CMs orientation. It did however induce a reorientation of cFBs, perpendicular to the strain direction, albeit this strain-avoidance response was overruled in the presence of anisotropic structural cues. These findings reveal that the mechanoresponsiveness of cFBs may be a critical handle in controlling myocardial tissue structure and function. To test this, we co-cultured hiPSC-CMs and cFBs in varying cell ratios to reconstruct normal and pathological myocardium. Contrary to the hiPSC-CM monoculture, the co-cultures adopted an anisotropic organization under uniaxial cyclic strain, regardless of the cell ratio. Together, these results identify the cFBs as a therapeutic target to mechanically restore structural organization of the tissue in cardiac regenerative therapies.SIGNIFICANCE STATEMENTUpon cardiac injury, adverse remodeling commonly leads to loss of the anisotropy that is typically found in human adult myocardium. Understanding the role of biophysical cues in shaping and disrupting the anisotropic tissue organization is essential to aid in the progress of cardiac regenerative strategies. Here, we report that the mechanoresponsiveness of cardiomyocytes (hiPSC-CMs) and cardiac fibroblasts (cFBs) differs significantly, resulting in a strain-induced reorganization response for cFBs but not for hiPSC-CMs. In co-culture with varying cell ratios of cFBs and hiPSC-CMs, the co-cultures adopted an anisotropic organization upon cyclic strain administration. Thus, our study proposes the mechanoresponse of cFBs, a cell type often overlooked in cardiac regenerative strategies, as a handle to restore myocardial architecture and function.

Sign in / Sign up

Export Citation Format

Share Document