Dataset Information

LC-MS/MS of conditioned media from vascularized tissue with and without cardiac microtissues.

ABSTRACT: Geometrically controlled cardiac microtissues promote vascularization and reduce inflammation in vitro and in vivo Cardiac tissue engineering faces challenges due to inadequate vascularization and lack of effective strategies to control inflammation post transplantation. . This study explores the benefits of geometrically optimized cardiac microtissues (μtissues) over dispersed cardiomyocytes (CMs) for in vitro and in vivo applications. Microtissues derived from human induced pluripotent stem cell-derived CMs (hiPSC-CMs) and compacted in between two PDMS pillars exhibit cellular alignment, contractile function and serve as suitable tissue building blocks. Constraining μtissue size to 300 µm ensures adequate oxygen diffusion, preventing necrotic core formation. In vivo, μtissues demonstrated improved engraftment, contractility, and vascularization in athymic nude rats, with significantly reduced inflammation and enhanced vessel ingrowth from the omental vasculature. This study highlights the potential of μtissues to advance cardiac tissue viability and function by creating contractile grafts with host endothelial ingrowth, offering a promising approach for cardiac repair and regeneration. When compared to dispersed CMs, μtissues show enhanced vessel network formation, reduced cell death (lower LDH), and decreased cytotoxicity (lower cell-free mtDNA). Cytokine analysis revealed elevated pro-angiogenic factors (PIGF, Endocan, Angiopoietin-2) and reduced inflammatory markers (IL-31 RA, IL-2 R beta, OX40 Ligand) in μtissues compared to dispersed CMs.

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ORGANISM(S): Homo Sapiens (human)

SUBMITTER: Michael Saikali

LAB HEAD: Carolyn L. Cummins

PROVIDER: PXD055832 | Pride | 2026-05-25

REPOSITORIES: Pride

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Geometrically controlled cardiac microtissues promote vascularization and reduce inflammation <i>in vitro</i> and <i>in vivo</i>.

Zhao Yimu Y Khosravi Ramak R Cheung Krisco K Shen Karen K Wang Ying Y Landau Shira S Okhovatian Sargol S Wu Qinghua Q Lu Rick Xing Ze RXZ Wagner Karl T KT Bodenstein David F DF Shawky Sarah A SA Vosoughi Daniel D Beroncal Erika Leigh EL Yeager Keith K Cummins Carolyn L CL Andreazza Ana C AC Vunjak-Novakovic Gordana G Radisic Milica M

Cell biomaterials 20250429 4

Cardiac tissue engineering faces challenges due to inadequate vascularization, poor engraftment, and ineffective strategies to control inflammation. This study explores the benefits of geometrically controlled cardiac microtissues over-dispersed cells. Microtissues derived from human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) and affixed between two polydimethylsiloxane (PDMS) pillars exhibited cellular alignment and contractile function and were necessary to serve as suita ...[more]

PMID: 40771434

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Project description:Primitive macrophages enhance a perivascular niche to enable vascular perfusion in human cardiac tissue The intricate anatomical structure and high cellular density of the myocardium significantly complicate the bioengineering of vascular networks within cardiac tissues, creating challenges in establishing a perfusable and stable vasculature within these tissues. Emerging evidence from murine in vivo studies underscores the significant role of resident cardiac macrophages in facilitating cardiac regeneration post-injury, specifically their role in enhancing angiogenesis. Here, for the first time, we integrate human pluripotent stem cell derived macrophages, resembling primitive yolk-sac derived macrophages, within human in vitro vascularized heart-on-chip platforms. The incorporation of primitive macrophages had a profound impact on the long term functionality of microvascularized cardiac tissue, particularly in enabling formation of perfusable vasculature with a stable barrier function that persisted for two weeks in culture. These effects were contingent on physical cell-cell interactions and significantly diminished in transwell culture. The inclusion of primitive macrophages mitigated tissue cytotoxicity and curtailed the release of cell-free mitochondrial-DNA, underscoring their indispensable role for mitigating cell damage in bioengineered tissues. Furthermore, their incorporation upregulated the secretion of pro-angiogenic, matrix remodeling and cardioprotective cytokines such as MMP-12, MMP-2, Angiopoietin-like 1, NRG-3, SIGIRR and Adiponectin. RNA sequencing disclosed upregulation of cardiac maturation (TTNI3, SCN5A, MYL2, and RYR2), and endothelial cells genes (PDGF-B, PECAM-1 and CDH5) as well as enhancement of angiogenic signaling, Wnt and PDGF pathways. Collectively, our results offer valuable insights into the integral role of primitive macrophages in directing long-term functional vascularization of cardiac tissues, paving the way for novel therapeutic strategies and advancing heart-on-a-chip systems.

Project description:The first macrophages that seed the developing heart originate from the yolk sac during fetal life. While murine studies reveal important homeostatic and reparative functions in adults, we know little about their roles in the earliest stages of human heart development due to a lack of accessible tissue. Generation of bioengineered human cardiac microtissues from pluripotent stem cells models these first steps in cardiac tissue development, however macrophages have not been included in these studies. To bridge these gaps, we differentiated human embryonic stem cells (hESCs) into primitive LYVE1+ macrophages (hESC-macrophages; akin to yolk sac macrophages) that stably engrafted within cardiac microtissues composed of hESC-cardiomyocytes and fibroblasts to study reciprocal interactions. Engraftment induced a tissue resident macrophage gene program resembling human fetal cardiac macrophages, enriched in efferocytic pathways. Functionally, hESC-macrophages induced production and maturation of cardiomyocyte sarcomeric proteins, and enhanced contractile force, relaxation kinetics, and electrical properties. Mechanistically, the primary effect of hESC-macrophages was during the stressful events surrounding early microtissue formation, where they engaged in phosphatidylserine dependent ingestion of apoptotic cardiomyocyte cargo, which reinforced core resident macrophage identity, reduced microtissue stress and drove hESC-cardiomyocytes to become more similar to human ventricular cardiomyocytes found in early development, both transcriptionally and metabolically. Inhibiting efferocytosis of hESC-cardiomyocytes by hESC-macrophages led to increased cell stress, impaired sarcomeric protein maturation and reduced cardiac microtissue function (contraction and relaxation). Taken together, macrophage-engineered human cardiac microtissues represent a considerably improved model for human heart development, and reveal a major beneficial, yet previously unappreciated role for human primitive macrophages in enhancing cardiac tissue function.

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Dataset Information

LC-MS/MS of conditioned media from vascularized tissue with and without cardiac microtissues.

Dataset's files

Publications

Geometrically controlled cardiac microtissues promote vascularization and reduce inflammation <i>in vitro</i> and <i>in vivo</i>.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

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Dataset Information

LC-MS/MS of conditioned media from vascularized tissue with and without cardiac microtissues.

Dataset's files

Publications

Geometrically controlled cardiac microtissues promote vascularization and reduce inflammation &lt;i&gt;in vitro&lt;/i&gt; and &lt;i&gt;in vivo&lt;/i&gt;.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Geometrically controlled cardiac microtissues promote vascularization and reduce inflammation <i>in vitro</i> and <i>in vivo</i>.