Metcela’s VCAM-1 positive cardiac fibroblast to play key roles in heart function improvement in ischemic heart failure by promoting lymphangiogenesis

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A new comprehensive study by Metcela, Inc. on human cardiac fibroblasts has revealed that VCAM1-positive cardiac fibroblasts (VCFs) play a crucial role in lymphangiogenesis in the injured myocardial tissue of ischemic heart failure, resulting in restoration of the mechanical properties of ventricular walls. Published in PLOS ONE are the results of in-vitro and in-vivo experiments clearly demonstrating the effects of VCF’s lymphangiogenesis using bioinformatic analyses, human cardiac lymphatic endothelial cell co-culture, and evaluation of human VCFs in nude rat heart failure model. These findings provide new insight to regenerative medicine’s promise in heart failure.

The non-clinical studies conducted by Metcela revealed at least two clear subpopulations of fibroblasts found in the human fetal heart: VCAM1-positive cardiac fibroblasts (VCFs) and VCAM1-negative cardiac fibroblasts (VNCFs). When examined with bioinformatics analyses, VCFs expressed numerous genes related to lymphatic vessel formation. Conversely, many of the genes expressed at higher levels in VNCFs were linked to fibrotic tissue formation. Lymphatic vascular formation assays showed significant stimulation of cardiac lymphatic cell network complexity, induced by VCFs compared to VNCFs. Recent studies have suggested that lymphangiogenesis improves cardiac function and repair by draining accumulated fluids and maintaining the physiological interstitial fluid equilibrium [1–3]. We hypothesized that VCFs may restore cardiac function in heart failure following myocardial infarction by enhancing lymphatic vessel formation.

Thus, to test whether lymphangiogenesis induced by VCFs can lead to improved mechanical properties and function of the heart, we performed in-vivo studies, in which human fetal heart-derived VCFs were injected into nude rat heart failure models with surgically induced myocardial infarction. The group that received VCF injection exhibited significant improvements in the cardiac function and restoration of the mechanical properties of ventricular walls by recruitment of lymphatic endothelial cells to the infarcts and subsequent lymphangiogenesis.

Further studies are underway to demonstrate the therapeutic effects of human adult heart-derived VCFs and identify the molecular signaling mechanisms that trigger lymphangiogenesis after treatment with VCFs.

This study was supported by grants from the New Energy and Industrial Technology Development Organization (NEDO).

1.     Henri O, Pouehe C, Houssari M, Galas L, Nicol L, Edwards-Lévy F, et al. Selective Stimulation of Cardiac Lymphangiogenesis Reduces Myocardial Edema and Fibrosis Leading to Improved Cardiac Function Following Myocardial Infarction. Circulation. 2016;133: 1484–1497. doi:10.1161/CIRCULATIONAHA.115.020143
2.     Shimizu Y, Polavarapu R, Eskla KL, Pantner Y, Nicholson CK, Ishii M, et al. Impact of lymphangiogenesis on cardiac remodeling after ischemia and reperfusion injury. J Am Heart Assoc. 2018;7: 1–14. doi:10.1161/JAHA.118.009565
3.     Uezumi A, Fukada S, Yamamoto N, Takeda S, Tsuchida K. Mesenchymal progenitors distinct from satellite cells contribute to ectopic fat cell formation in skeletal muscle. Nat Cell Biol. 2010;12: 143–152. doi:10.1038/ncb2014

■About the article
Title: “Human cardiac fibroblasts expressing VCAM1 improve heart function in postinfarct heart failure rat models by stimulating lymphangiogenesis”
Authors: Takahiro Iwamiya, Bertrand-David Segard, Yuimi Matsuoka, Tomomi Imamura

■About VCF
Metcela discovered VCAM-1-positive Cardiac Fibroblast (VCF), a specific type of fibroblast that re-establishes a favorable microenvironment for regeneration and cardiac contractile function restoration within the damaged heart tissues. VCFs can easily be cultured and are now known to induce lymphangiogenesis and stimulate proliferation of cardiomyocytes to regenerate the damaged tissues of the heart. Metcela’s intellectual property on VCFs is covered by several patents (JP6241893 and JP6618066). Metcela plans to initiate an investigator-initiated Phase I clinical trial for autologous VCF in early 2021.

Corporate Overview
Headquarter: Tsuruoka-shi, Yamagata
Research Center: Life Innovation Center: 3-25-22 Tonomachi; Kawasaki-ku, Kawasaki-shi, Kanagawa 210-0821; Japan
Co-CEOs: Takahiro Iwamiya, Kenichi Nogami
Foundation: March 2016

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Ami Okuno
Metcela Inc.
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