A three-dimensional <i>in vitro</i> dynamic micro-tissue model of cardiac scar formation

Occhetta, Paola; Isu, Giuseppe; Lemme, Marta; Conficconi, Chiara; Oertle, Philipp; Räz, Christian; Visone, Roberta; Cerino, Giulia; Plodinec, Marija; Rasponi, Marco; Marsano, Anna

doi:10.1039/c7ib00199a

Cited by 37 publications

(48 citation statements)

References 39 publications

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“…In addition to engineered normal cardiac tissues on chip, establishment of in vitro pathological tissue models is crucial for applications in diseases studies and drug development. A hydrogel‐based cardiac scar‐on‐a‐chip model was developed to recapitulate the key features of scar formation including fibroblast proliferation and activation, ECM deposition and stiffening . In another study, neonatal cardiac fibroblasts were embedded in 3D fibrin hydrogels, then applied with mechanical stimulation (cyclic stretching) to mimic a fibrosis‐like environment .…”

Section: Hydrogels In Organs‐on‐a‐chip Engineeringmentioning

confidence: 99%

Advances in Hydrogels in Organoids and Organs‐on‐a‐Chip

et al. 2019

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The major motivation is to better mimic human physiology and functions at multiscales from the molecular to the cellular, tissue, organ or even whole organism level. Current model systems primarily rely on the monolayer cell cultures and animal models. Simplistic monolayer cultures have their advantages, but they are often significantly different in gene expression, epigenetics, and cell function compared to native 3D tissues. [1,2] Also, they often lack cell-cell and cell-matrix interactions, [2,3] leading to the absence of tissue specific properties. Although animal models are widely used in biomedical research, they fail to faithfully predict human responses in a physiologically relevant manner due to the significant species divergences. [4] The limitations of these systems have provided an impetus for the development of alternative cell-based 3D models in vitro that better resemble the complex functionalities of living organs. Over the last several years, organoids and organ-on-a-chip (OOC), representing the major technological breakthrough, have emerged as two distinct model systems to achieve the same goal of building 3D organotypic models in vitro by bridging the gap between animal models and monolayer cultures. These engineered models are different in terms of cell source, tissue composition, architectural variability, functional features, scales, cellular fidelity, etc. Organoids, primarily evolving from developmental principles, refer to 3D multicellular tissues by self-organization of stem cells or organ-specific progenitors, which can recapitulate the intricate architectures and functionalities of in vivo organs. [5][6][7] Recent breakthroughs in organoid technology have enabled the successful generation of a variety of human organoids, such as the brain, [8,9] intestine, [10,11] liver, [12] kidney, [13,14] lung, [15] etc. These near physiological 3D organoids have garnered momentum for their potential applications in human organ development and disease modeling, drug screening and regenerative medicine. The explosion of organoids research has been catalyzed by the significant progress of stem cell biology and availability of human stem cells. In contrast, the OOC, relying on the bioengineering design principle, is a miniaturized in vitro model that can recreate the functional units of living organs on a microfluidic cell culture device using predifferentiated cells, often cell lines. [1,16] The OOC is primarily evolved from the convergence of tissue engineering and microfabricated technologies, which is characterized by the capability to simulate cellular microenvironment by precise control over fluid flow, mechanical forces and biochemical factors. [4,17] Remarkable progress has been made Significant advances in materials, microscale technology, and stem cell biology have enabled the construction of 3D tissues and organs, which will ultimately lead to more effective diagnostics and therapy. Organoids and organs-on-a-chip (OOC), evolved from developmental biology and bioengineering principles, have e...

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Section: Hydrogels In Organs‐on‐a‐chip Engineeringmentioning

confidence: 99%

Advances in Hydrogels in Organoids and Organs‐on‐a‐Chip

et al. 2019

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“…The reversibility of this low-oxygen-induced condition was confirmed by the fact that the subsequent treatment with fresh growth medium and high-oxygen tension partially recovered CM organization and electrical functionality. Concomitantly, we observed that fibroblasts switched their phenotype towards myofibroblasts as usually observed during cardiac remodeling inflammatory/repair processes (Diaz-Flores et al, 2015;Li et al, 2015;Occhetta et al, 2018). A similar 2D model had never been developed, and can be a useful screening tool for testing and screening therapeutic factors.…”

Section: Discussionmentioning

confidence: 52%

“…This condition is different from the ischemia-reperfusion injury in which, following ischemia, the sudden restore of the oxygen levels by reperfusion could paradoxically cause more damage to the cardiomyocytes due to multifactorial mechanisms (as calcium overload and reactive oxygen species overproduction; Kalogeris, Bao, & Korthuis, 2014). Concomitantly, we observed that fibroblasts switched their phenotype towards myofibroblasts as usually observed during cardiac remodeling inflammatory/repair processes (Diaz-Flores et al, 2015;Li et al, 2015;Occhetta et al, 2018). Second, this 2D model was used to investigate the potential SVF paracrine effect on chronic hibernating CM, evaluating the consequent CM recovery in morphology and functionality.…”

Section: Discussionmentioning

confidence: 55%

Paracrine potential of adipose stromal vascular fraction cells to recover hypoxia‐induced loss of cardiomyocyte function

Mytsyk

Isu

Cerino

et al. 2018

Biotech & Bioengineering

Self Cite

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Cell-based therapies show promising results in cardiac function recovery mostly through paracrine-mediated processes (as angiogenesis) in chronic ischemia. In this study, we aim to develop a 2D (two-dimensional) in vitro cardiac hypoxia model mimicking severe cardiac ischemia to specifically investigate the prosurvival paracrine effects of adipose tissue-derived stromal vascular fraction (SVF) cell secretome released upon three-dimensional (3D) culture. For the 2D-cardiac hypoxia model, neonatal rat cardiomyocytes (CM) were cultured for 5 days at < 1% (approaching anoxia) oxygen (O ) tension. Typical cardiac differentiation hallmarks and contractile ability were used to assess both the cardiomyocyte loss of functionality upon anoxia exposure and its possible recovery following the 5-day-treatment with SVF-conditioned media (collected following 6-day-perfusion-based culture on collagen scaffolds in either normoxia or approaching anoxia). The culture at < 1% O for 5 days mimicked the reversible condition of hibernating myocardium with still living and poorly contractile CM (reversible state). Only SVF-medium conditioned in normoxia expressing a high level of the prosurvival hepatocyte-growth factor (HGF) and insulin-like growth factor (IGF) allowed the partial recovery of the functionality of damaged CM. The secretome generated by SVF-engineered tissues showed a high paracrine potential to rescue the nonfunctional CM, therefore resulting in a promising patch-based treatment of specific low-perfused areas after myocardial infarction.

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“…In addition to thrombosis, fibrosis has also been modeled in vitro through the application of cyclic mechanical stretching to cell‐laden hydrogels, resulting in fibroblast differentiation, matrix protein deposition, ECM stiffening, and remodeling of scar tissue. [ 332,341,342 ] These in vitro mechanistic studies which can elucidate the role of biophysical forces in driving aberrant cardiovascular pathologies have significant potential for the development of life‐saving interventions and clinical translation from bench to bedside. [ 340,343 ] However, further mechanistic insight into the developmental stages of cardiac disorders needs to be obtained via the use of cardiac‐specific ECs or hiPSC‐derived ECs differentiated toward cardiac‐specific phenotype and their functional incorporation in microphysiological systems.…”

Section: Modeling Vascular Mechanopathology In Vascularized Microphysmentioning

confidence: 99%

Biofabrication Strategies and Engineered In Vitro Systems for Vascular Mechanobiology

Pradhan

Banda

Farino

et al. 2020

Adv Healthcare Materials

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The vascular system is integral for maintaining organ‐specific functions and homeostasis. Dysregulation in vascular architecture and function can lead to various chronic or acute disorders. Investigation of the role of the vascular system in health and disease has been accelerated through the development of tissue‐engineered constructs and microphysiological on‐chip platforms. These in vitro systems permit studies of biochemical regulation of vascular networks and parenchymal tissue and provide mechanistic insights into the biophysical and hemodynamic forces acting in organ‐specific niches. Detailed understanding of these forces and the mechanotransductory pathways involved is necessary to develop preventative and therapeutic strategies targeting the vascular system. This review describes vascular structure and function, the role of hemodynamic forces in maintaining vascular homeostasis, and measurement approaches for cell and tissue level mechanical properties influencing vascular phenomena. State‐of‐the‐art techniques for fabricating in vitro microvascular systems, with varying degrees of biological and engineering complexity, are summarized. Finally, the role of vascular mechanobiology in organ‐specific niches and pathophysiological states, and efforts to recapitulate these events using in vitro microphysiological systems, are explored. It is hoped that this review will help readers appreciate the important, but understudied, role of vascular‐parenchymal mechanotransduction in health and disease toward developing mechanotherapeutics for treatment strategies.

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A three-dimensional in vitro dynamic micro-tissue model of cardiac scar formation

Cited by 37 publications

References 39 publications

Advances in Hydrogels in Organoids and Organs‐on‐a‐Chip

Advances in Hydrogels in Organoids and Organs‐on‐a‐Chip

Paracrine potential of adipose stromal vascular fraction cells to recover hypoxia‐induced loss of cardiomyocyte function

Biofabrication Strategies and Engineered In Vitro Systems for Vascular Mechanobiology

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