Stromal Cell Biology - A Way to Understand the Evolution of Cardiovascular Diseases -

Tsuruda, Toshihiro; Imamura, Takuroh; Hatakeyama, Kinta; Asada, Yujiro; Kïtamura, Kazuo

doi:10.1253/circj.cj-10-0024

Cited by 11 publications

(7 citation statements)

References 125 publications

(67 reference statements)

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“…Traditionally, cardiac fibroblasts were defined by their morphological appearance, namely by their branched cytoplasm surrounding an elliptical, speckled nucleus that typically has 1 or 2 nucleoli. 1,2,21 However, study of cardiac fibroblasts has been challenging, and they remain poorly characterized in molecular terms. 1 One reason for this is the relative lack of serviceable fibroblast markers, because the known markers either are not specific for fibroblasts or detect only subpopulations of fibroblasts.…”

Section: Challenges Of Studying Fibroblasts In the Heartmentioning

confidence: 99%

“…1,2 With their various functions, cardiac fibroblasts are at the interface of multiple interactions, playing an integral part in maintaining homeostasis in the heart. 3,4 Under physiological conditions, cardiac fibroblasts contribute to the structural, mechanical, biochemical, and electric properties of the heart.…”

mentioning

confidence: 99%

“…Importance of fibroblasts in cardiac pathology is even more obvious, because fibroblasts are considered the predominant source of the extracellular matrix, the hallmark of fibrosis 1,2,6,16 Most cardiac diseases are associated with an increase of fibrosis in the heart. 17 Fibrosis of the cardiac tissue has significant consequences on cardiac function.…”

mentioning

confidence: 99%

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Origins of Cardiac Fibroblasts

Zeisberg

Kalluri

2010

Circulation Research

209

190

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Cardiac fibroblasts play a critical role in maintenance of normal cardiac function. They are indispensable for damage control and tissue remodeling on myocardial injury and principal mediators of pathological cardiac remodeling and fibrosis. Despite their manyfold functions, cardiac fibroblasts remain poorly characterized in molecular terms. Evidence is evolving that cardiac fibroblasts are a heterogeneous population and likely derive from various distinct tissue niches in health and disease. Here, we review our emerging understanding of where cardiac fibroblasts come from, as well as how we can possibly use this knowledge to develop novel therapies for cardiac fibrosis.

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Section: Challenges Of Studying Fibroblasts In the Heartmentioning

confidence: 99%

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confidence: 99%

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Origins of Cardiac Fibroblasts

Zeisberg

Kalluri

2010

Circulation Research

209

190

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“…Kadner et al found that umbilical cord artery derived cells express cytoskeletal filament proteins such as alpha smooth muscle actin (ASMA) and fibroblastic vimentin and additionally show fibroblast like morphology. For this reason they were considered to be myofibroblasts [12], an intermediate cell type between fibroblast and smooth muscle cells [13,14]. A comparative study revealed that CD90, fibronectin and collagen type I expression of human umbilical cord artery derived cells is similar to that of pulmonary heart valve interstitial cells.…”

Section: Introductionmentioning

confidence: 99%

Cryopreservation of human vascular umbilical cord cells under good manufacturing practice conditions for future cell banks

et al. 2012

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BackgroundIn vitro fabricated tissue engineered vascular constructs could provide an alternative to conventional substitutes. A crucial factor for tissue engineering of vascular constructs is an appropriate cell source. Vascular cells from the human umbilical cord can be directly isolated and cryopreserved until needed. Currently no cell bank for human vascular cells is available. Therefore, the establishment of a future human vascular cell bank conforming to good manufacturing practice (GMP) conditions is desirable for therapeutic applications such as tissue engineered cardiovascular constructs.Materials and methodsA fundamental step was the adaption of conventional research and development starting materials to GMP compliant starting materials. Human umbilical cord artery derived cells (HUCAC) and human umbilical vein endothelial cells (HUVEC) were isolated, cultivated, cryopreserved (short- and long-term) directly after primary culture and recultivated subsequently. Cell viability, expression of cellular markers and proliferation potential of fresh and cryopreserved cells were studied using trypan blue staining, flow cytometry analysis, immunofluorescence staining and proliferation assays. Statistical analyses were performed using Student’s t-test.ResultsSufficient numbers of isolated cells with acceptable viabilities and homogenous expression of cellular markers confirmed that the isolation procedure was successful using GMP compliant starting materials. The influence of cryopreservation was marginal, because cryopreserved cells mostly maintain phenotypic and functional characteristics similar to those of fresh cells. Phenotypic studies revealed that fresh cultivated and cryopreserved HUCAC were positive for alpha smooth muscle actin, CD90, CD105, CD73, CD29, CD44, CD166 and negative for smoothelin. HUVEC expressed CD31, CD146, CD105 and CD144 but not alpha smooth muscle actin. Functional analysis demonstrated acceptable viability and sufficient proliferation properties of cryopreserved HUCAC and HUVEC.ConclusionAdaptation of cell isolation, cultivation and cryopreservation to GMP compliant starting materials was successful. Cryopreservation did not influence cell properties with lasting impact, confirming that the application of vascular cells from the human umbilical cord is feasible for cell banking. A specific cellular marker expression profile was established for HUCAC and HUVEC using flow cytometry analysis, applicable as a GMP compliant quality control. Use of these cells for the future fabrication of advanced therapy medicinal products GMP conditions are required by the regulatory authority.

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“…12–15,51 Marked phenotypic alterations in fibroblast adhesion and migration have been correlated with myocardial disease. 52–55 Cardiac fibroblasts can also secrete vitronectin and express vitronectin receptor α V β 3 integrin.…”

Section: Discussionmentioning

confidence: 99%

Vitronectin-binding PAI-1 protects against the development of cardiac fibrosis through interaction with fibroblasts

Zhong

Yang

Kon

et al. 2014

Laboratory Investigation

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Plasminogen activator inhibitor-1 (PAI-1) promotes or abates fibrotic processes occurring in different organs. Binding of PAI-1 to vitronectin, an extracellular matrix component, may inhibit vitronectin–integrin complex-mediated cellular responses in pathophysiological conditions. To investigate the importance of plasmin suppression vs vitronectin-binding pathways of PAI-1 in cardiac fibrosis, we studied uninephrectomized mice fed a high salt diet and infused with angiotensin II (Ang II) together with different PAI-1 variants, including PAI-1AK (AK) that inhibits plasminogen activators but does not bind vitronectin, PAI-1RR (RR) that binds vitronectin but does not have protease inhibitory effects or control PAI-1 (CPAI), the control mutant that has similar molecular backbone and half-life as AK and RR while retaining all functions of native PAI-1. Compared with RR and CPAI, non-vitronectin-binding AK significantly increased expression of cardiac fibroblast marker, periostin (Ang + AK 8.40± 3.55 vs Ang RR 2.23 ± 0.44 and Ang CPAI 2.33 ± 0.12% positive area, both P <0.05) and cardiac fibrosis (Ang + AK 1.79 ± 0.26% vs Ang + RR 0.91 + 0.18% and Ang + CPAI 0.81 ± 0.12% fibrotic area, both P <0.05), as well as Col1 mRNA (Ang + AK 12.81 ± 1.84 vs Ang + RR 4.04 ± 1.06 and Ang + CPAI 5.23 ± 1.21 fold increase, both P <0.05). To elucidate mechanisms underlying the protective effects of vitronectin-binding PAI-1 against fibrosis, fibroblasts from normal adult human ventricles were stimulated with Ang and different PAI-1 variants. Protease inhibitory AK and CPAI increased supernatant fibronectin, while decreasing plasminogen activator/plasmin activities and matrix metalloproteinase. RR and CPAI variants significantly reduced fibroblast expression of integrin β3, vitronectin level in the supernatant and fibroblast adhesion to vitronectin compared with the non-vitronectin-binding AK. Further, RR and CPAI preserved apoptotic, decreased anti-apoptotic and proliferative activities in fibroblasts. Thus, PAI-1 promotes or protects against development of cardiac fibrosis differentially through the protease inhibitory pathway or through its binding to vitronectin.

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Stromal Cell Biology - A Way to Understand the Evolution of Cardiovascular Diseases -

Cited by 11 publications

References 125 publications

Origins of Cardiac Fibroblasts

Origins of Cardiac Fibroblasts

Cryopreservation of human vascular umbilical cord cells under good manufacturing practice conditions for future cell banks

Vitronectin-binding PAI-1 protects against the development of cardiac fibrosis through interaction with fibroblasts

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