When the supply of oxygen to the heart is reduced, its cells start to die within hours, the heart muscle becomes less able to contract, and the area becomes inflamed. This inflammation is accompanied by an influx of immune cells. It also activates other cells known as cardiac fibroblasts that help to break down the framework of molecules that supported the damaged heart tissue and replace it with a scar. This response is part of the normal repair process, but it can lead to the formation of scar tissue in non-damaged areas of the heart. Excess scar tissue makes the heart muscle less able to contract and increases the affected individual’s chance of dying.

Understanding how this repair process works is an important step in developing strategies to minimise the damage caused by coronary artery disease or heart attacks. However, existing laboratory models are only partly able to recreate the conditions seen in real heart tissue. To properly understand the response at the level of living cells, a more complete model is needed.

Ugolini et al. now report improvements to a small device, referred to as a lab-on-chip, that can subject cells to mechanical strain. The improvements mean the device could also recreate other conditions seen early on in damaged heart tissue, specifically the reduced supply of oxygen. Replicating combinations of mechanical changes and oxygen supplies meant that the impact of these conditions on human cardiac fibroblasts could be directly observed in the laboratory for the first time. Ugolini et al. found that a lack of contraction and low oxygen levels triggered the cardiac fibroblasts to produce inflammatory molecules and molecules associated with the formation of scar tissue. This resembles the response seen in living hearts.

The next step is to improve the lab-on-chip device further by adding other cell types, including heart muscle cells and immune cells. A more complete model may aid future research into how our hearts operate in both health and disease.

When supply of oxygen and nutrients to the myocardium is critically reduced (ischemia), a complex tissue response takes place: within hours tissue necrosis and death of contractile cardiac myocytes occurs in the infarcted area giving rise to an inflammatory phase that recruits immune cells and activates quiescent cardiac fibroblasts (CFs); within a few days a proliferative phase begins, where activated CFs invade the infarcted area and contribute to degrading and replacing the extra-cellular matrix with a collagen-based scar; within weeks the maturation of the fibrotic scar is completed (Frangogiannis, 2014; Heusch et al., 2014). Cellular and molecular events such as excessive proliferation of CFs, phenotypic switch of CFs, high levels of inflammatory cytokines and humoral factors, unbalanced synthesis of extracellular matrix (ECM) proteins and matrix metalloproteinases (MMP)-mediated degradation of ECM are generally regarded as hallmarks of early fibrotic tissue response (Fan et al., 2012; Krenning et al., 2010; Porter and Turner, 2009; Shinde and Frangogiannis, 2014). This essential process maintains tissue integrity, however, it often leads to excessive and adverse CFs remodeling of non-infarcted areas (Fan et al., 2012; Kania et al., 2009; Talman and Ruskoaho, 2016) associated with cardiac dysfunction and increased mortality (Okada et al., 2005). Controlled anti-fibrotic strategies still require deeper understanding and advanced models of cardiac fibrosis mechanisms (Leask, 2010; Roubille et al., 2014).

In general, the onset of pathological myocardial conditions causes alterations of specific environmental cues at the cellular scale: mechanical strain decreases (loss of contractility); oxygen and nutrient levels dramatically decrease (ischemia); levels of inflammatory cytokines increase (post-injury inflammatory response). In an attempt to provide in vitro models of cardiac disease, CFs have been widely studied under relevant physico-chemical stimulation such as mechanical stress (Schroer and Merryman, 2015; Tomasek et al., 2002), oxygen deprivation (Clancy et al., 2007; Tamamori et al., 1997) and biochemical stimulation with pro-fibrotic cytokines (Edgley et al., 2012; Lijnen et al., 2000; Petrov et al., 2002). The application of mechanical stress has been shown to have the following effects on CFs: increased ECM protein synthesis (Carver et al., 1991); controversial proliferative behavior (Atance et al., 2004; Butt and Bishop, 1997; Dalla Costa et al., 2010; Liao et al., 2004), with recent reports of strain intensity-dependent effects (Ugolini et al., 2016); increased production of pro-fibrotic and inflammatory cytokines such as TGF-β (transforming growth factor-beta) (Leask, 2007) and TNF-α (tumor necrosis factor-alpha) (Yokoyama et al., 1999).

While previous mechanical stress experiments were performed in a normoxic environment (NX, approximately 20% O₂, the standard oxygen level of ambient air), CFs were shown to be sensitive to O₂ level variations from physoxia (PX), defined as the physiologic oxygen level in living tissues (about 5–6% O₂ in the myocardium [Gonschior et al., 1992; Roy et al., 2003; Sen et al., 2006; Winegrad et al., 1999]). Both hypoxia (HX, 1–3% O₂) and NX induce a pro-inflammatory and fibrogenic phenotype in cultured CFs (Roy et al., 2003; Sen and Roy, 2010). These findings imply that normoxic oxygen levels are perceived by CFs as a state of hyperoxia and that a significant bias exists when culturing CFs in non-physiological oxygen environments. The exposure of CFs to HX has been shown to induce collagen production and proliferation of CFs (Gao et al., 2014; Tamamori et al., 1997), while studies suggest that MMP-based remodeling may not be triggered by HX alone (Riches et al., 2009).

Given the complexity of in vivo pathological evolution, the elucidation of how environmental stimuli interplay and guide cellular responses is paramount. To date, no comprehensive model is able to recapitulate early cellular events taking place after acute myocardial injury and there is no report of cardiac cells subjected to simultaneous mechanical strain and controlled oxygen changes, two major environmental variables involved in cardiac injury and CF adaptive responses. This is mostly due to the lack of compact platforms enabling the controlled application of multiple stimuli.

To address this need, we here report the improvement of a previously described multi-chamber microdevice dedicated to the application of cyclic strain to cell monolayers (Ugolini et al., 2016). By adding a system for controlling oxygen changes, we significantly expanded the experimental complexity and mimicking capabilities of the device. We here finely controlled the applied mechanical strain and oxygen regimes sensed by CFs to model early environmental changes in cardiac injury and provide insights into individual or synergistic contributions of the environmental signals in the activation of early CF responses relevant to cardiac fibrotic disease. Shortly after an ischemic myocardial insult (e.g., acute coronary artery occlusion) tissue oxygen levels drop from approximately 5–6% O₂ (Gonschior et al., 1992; Sen et al., 2006; Winegrad et al., 1999) to near-zero (Roy et al., 2003), rapidly inducing loss of cardiac myocytes contractility. In terms of in vitro model parameters, we thus selected 5% O₂ (PX) as a physiological oxygen level and 1% O₂ (HX) as an oxygen level characteristic of ischemic myocardial injury. Dramatic alterations of injured myocardial tissue also take place in early timeframes: tissue bulging and dilations are commonly observed together with loss of contractile function (Eek et al., 2010; Pfeffer and Braunwald, 1990; Picard et al., 1990; Tennant and Wiggers, 1935). Cardiac imaging studies agree in the interpretation that global strains are abruptly reduced shortly after myocardial insult (Flachskampf et al., 2011; Hoit, 2011; Mollema et al., 2010). Quantitatively, strain values recorded vary significantly throughout the heart. Although absolute values may depend on imaging algorithms, strains in ischemic/injured regions have been reported to be 2–4 fold lower than in healthy myocardial regions (e.g. less than 3% in ischemic regions versus approximately 10% in healthy regions [Dandel et al., 2009; Vartdal et al., 2007]). Within this range and in line with previous in vitro observations of CFs behavior (Ugolini et al., 2016), we selected 2% strain as indicative of reduced contractility and 8% strain as representative of full myocardial contractility. These environmental changes and the following initial cellular responses happen in a timeframe of hours, as shown in vitro (van Nieuwenhoven et al., 2013; Turner et al., 2007, 2009) as well as in vivo (Guillén et al., 1995; Morishita et al., 2015). We thus performed experiments lasting 24 hr and evaluated the main early aspects that govern fibrotic responses in the injured myocardium: ECM remodeling, with stainings for collagen I and quantifications of MMP expression; proliferation of CFs, with analyses of mitotic cells, Hippo pathway signaling and mitogenic PDGF (platelet-derived growth factor) expression; secretion of inflammatory and pro-fibrotic cytokines in CF supernatants; myofibroblast differentiation, through stainings for αSMA (α-smooth muscle actin). Results of our investigation provide insights into how the combination of environmental stimuli may act synergistically or independently to drive in vitro adaptive early CF responses.

Microenvironmental changes taking place in the injured myocardium trigger tissue responses that are orchestrated between multiple cell types (mainly cardiac myocytes, cardiac fibroblasts and immune cells) and involve multiple cell functions and signaling pathways. The outcome of this process is a substantial remodeling of the injured myocardial region by ECM-producing CFs that often results in excessive and dysfunctional alterations of the myocardial architecture and functionality. The elucidation of pathological cellular routes leading to tissue-level failure can clearly benefit from effective in vitro studies capable of dissecting and analyzing responses to multiple physiological and pathological conditions. Microfluidic technologies have recently enabled the development of advanced cardiac models by integrating key environmental cues in cardiac cell cultures (Agarwal et al., 2013; Marsano et al., 2016; Pavesi et al., 2015; Uzel et al., 2014). We here investigated CF behaviors in a compact multi-chamber in vitro platform designed to perform cell cultures under combined mechanical stimulation and changes in oxygen levels. This novel tool enabled us to perform for the first time a systematic evaluation of early CF responses to the combination of oxygen levels and mechanical strain regimes that facilitate a more realistic model of cardiac physiology and pathology.

Despite being overlooked in most previous studies, rigorous replication of in vivo oxygen tensions proved fundamental for interpreting physiological and pathological CF responses (Roy et al., 2003). Two oxygen conditions were tested: physiological oxygen levels experienced by CFs in the myocardium (5% O₂, PX) and a rapid decrease of oxygen levels resembling an acute ischemic event (1% O₂, HX). We also performed analyses on CFs cultured under non-physiological normoxic (NX) conditions and confirmed a substantial impact of NX compared to PX, especially on cell proliferation.

The mechanical microenvironment is known to change upon cardiac injury. It is known that injured myocardial regions are characterized by an early reduction of mechanical load due to loss of contractile cardiac myocytes (Eek et al., 2010; Pfeffer and Braunwald, 1990; Picard et al., 1990; Tennant and Wiggers, 1935). We therefore focused on evaluating how significant changes in mechanical strain affect cellular responses. To explore these effects we employed low cyclic strain mimicking reduced contractility (2% strain), physiological cyclic strain (8% strain) and a static control. These values were based on cardiac imaging studies performed shortly after myocardial injury (Dandel et al., 2009; Vartdal et al., 2007) and were previously reported to elicit strain-dependent effects in CFs (Ugolini et al., 2016).

Pathological remodeling of the myocardium involves activation of multiple CF cell functions. In a significant step forward compared to previous studies, our analyses encompassed most known pathological responses of CFs: production of ECM proteins and ECM-remodeling enzymes, cellular proliferation, secreted pro-fibrotic or inflammatory cytokines and myofibroblast differentiation. This in-depth assessment demonstrates how environmental factors participate in driving CF pathological responses and elucidates the existence of separate and synergistic roles of mechanical stimulation and oxygen levels in directing cellular functions relevant to early phases of cardiac fibrotic remodeling.

Our findings demonstrated that upon sensing of hypoxic environments CFs quickly (<24 hr) activate proliferative responses (Table 1). We propose that the increase in cell proliferation is mediated by the Hippo pathway given the correlation between nuclear YAP translocation and mitotic cells (PHH3⁺). YAP is widely recognized as a key factor in cardiac repair (Papizan and Olson, 2014; Xin et al., 2013). We found, however, that in contrast with other studies performed at NX (Codelia et al., 2014), YAP nuclear translocation is not related to increasing cyclic mechanical strain. In addition, an increased secretion of mitogenic PDGF by CFs at HX suggests a possible autocrine CF mechanism aimed at modulating proliferation upon pathological myocardial conditions.

We also showed that hypoxia alone causes an increased collagen presence in CFs cultures. This is consistent with data obtained in previous works focused on collagen production by CFs subject to HX (Tamamori et al., 1997). We therefore demonstrated how HX alone induces pro-fibrotic responses in CFs.

A significant novel insight observed in the present study is that the combination of HX and mechanical strain incrementally instructed further pathological cell responses. Indeed, the production of pro-fibrotic TGF-β, inflammatory cytokine IL1-β and matrix-degrading enzymes (MMP-2 and MMP-3) significantly increased only when cells were subject to combined HX and low levels of cyclic strain (HX/2% strain). TGF-β is markedly upregulated in vivo in regions of cardiac tissue injury and is known to act in vitro on CFs phenotypic switch, proliferation and collagen synthesis (Leask, 2007; Lijnen et al., 2000). IL1-β has been described in vivo as an early (<10 hr) post-injury inflammatory cytokine (Guillén et al., 1995) and CFs are thought to be one of the main cellular sources of IL1-β (Turner, 2014). MMPs are known to be primarily involved in the remodeling of the injured myocardium and it is worth noting that previous studies reported inhibitory effects of HX alone on MMP expression (Riches et al., 2009). In another study, mechanical stress did not alter MMP expression unless cells were cultured in serum deprivation (Tyagi et al., 1998). This context strengthens the hypothesis of a combined contribution of environmental conditions in driving MMP secretion by CFs, and the importance of reproducing complex environmental changes in vitro. In addition, literature suggests a direct effect of TGF-β and IL1-β on the expression of MMPs in CFs (Brown et al., 2007; Stawowy et al., 2004) and we observed how the expression levels of TGF-β and IL1-β under combined stimulation are in line with the altered expression of MMPs. Further studies may therefore be directed towards the elucidation of such possible autocrine mechanisms regulating CFs-mediated ECM remodeling. Notably, no experimental condition led to myofibroblast differentiation, with the exception of the positive control (additional biochemical stimulation with TGF-β), thus highlighting the importance of soluble pro-fibrotic factors for this aspect of CF pathological activation.

Intriguingly, we found that when cells were subject to physiological cyclic strain (8% strain) together with HX condition, most of the above pathological CF responses were not observed and we found only a modest increase in collagen presence. Similarly, when oxygen conditions resemble those of healthy tissue (PX), cyclic mechanical strain only results in increased collagen presence (at 8% strain) or in increased proliferation (at 2% strain). These results are in line with previous studies (performed in NX environments) on mechanically stimulated CFs (Carver et al., 1991; Husse et al., 2007; Ugolini et al., 2016).

Overall, these outcomes suggest that CFs respond differently to different regimes of cyclic strain, to different oxygen conditions and to combinations of these. In the context of an acute myocardial insult, loss of contractility and decrease in sensed oxygen levels are able to instruct a consistent response of CFs that involves matrix remodeling, inflammatory and proliferative behaviors. Our combined conditions allowed us to report that a mechanical environment resembling full contractility (8% strain) may hold a protective potential and resulted in attenuating CFs inflammatory, remodeling and pro-fibrotic responses taking place in HX.

These findings help to validate an on-chip model capable of exploring in vitro early fibrotic responses elicited in the injured myocardium. To estimate how this novel approach quantitatively correlates with standard readouts associated with cardiac fibrotic responses, we compared the fold changes of CF markers assessed in our model to those observed in standard in vitro models. Standard approaches typically involve the biochemical stimulation of CFs with known concentrations of pro-fibrotic (e.g., TGF-β) or inflammatory (e.g., interleukins) molecules. We collected literature studies where protein expression of relevant markers was measured at early stages of CFs culture under pro-fibrotic/inflammatory conditions. Table 2 shows quantitative comparisons between standard models and our on-chip model. Our model correlates well with quantitative readouts involving ECM, ECM-remodeling enzymes (collagen and MMPs expression) and proliferative effects, although contradictory studies also showed decreased CF proliferation under pro-fibrotic stimuli. Notably, MMP levels in serum were shown to increase by approximately two-fold in patients after 24 hr from acute myocardial injury diagnosis (Morishita et al., 2015). As for CF secretion of pro-fibrotic and inflammatory factors, our model was able to capture the triggering of PDGF expression by CFs, an aspect not yet described by standard in vitro approaches. Interestingly, this also correlated with in vivo increments in plasma levels of PDGF (approximately two-fold increment) at the early onset (12 hr) of myocardial injury in human patients (Koizumi et al., 2015). Additionally, our results correlated with secretion of TGF-β and IL-1β, while our environment-based model did not induce significant changes to the secreted levels of IL-6 and TNF-α as in standard models.

This last missing readout suggests that indirect paracrine action provided by other cellular actors involved in myocardial homeostasis and typically modeled in standard biochemical stimulation approaches is likely to play a role in driving the inflammatory responses that are not captured in our model. For instance, immune cells such as monocytes or macrophages are known to infiltrate the injured myocardium, supporting the inflammatory environment and providing additional paracrine cytokines to CFs (van Amerongen et al., 2007; Frantz et al., 2013; Nahrendorf et al., 2010). In addition, cross talk between cardiac myocytes and CFs has been widely described (Cartledge et al., 2015; Zhang et al., 2012) and shown to drive CF behaviors such as myofibroblast differentiation(Tsoporis et al., 2012) and increased production of inflammatory molecules (Bowers et al., 2010). These indirect mechanisms could help evoke additional responses not captured in our model or could increase to an even greater magnitude the ones that we described as driven by environmental signals. Direct effects of cardiomyocyte contractility also mechanically influence CF behavior in vivo, however, this aspect is recreated in vitro by our system that exposes cultured CFs to uniform but tunable mechanical signals, thus proving advantageous for improving the clarity of readouts. Further improvements to the current model, such as the addition of paracrine signaling with other cell types, represents a promising future direction for this work, with the aim of developing a more accurate on-chip model combining fine control over the microenvironment with realistic biochemical signaling.

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Author details

1. Giovanni Stefano Ugolini

   Department of Electronics, Information and Bioengineering, Politecnico di Milano, Milan, Italy

   Contribution

   GSU, Conceptualization, Investigation, Methodology, Writing—original draft, Writing—review and editing

   Competing interests

   The authors declare that no competing interests exist.

   "This ORCID iD identifies the author of this article:" 0000-0003-4775-6676

2. Andrea Pavesi

   1. Institute of Molecular and Cell Biology, Agency for Science, Technology and Research, Singapore, Singapore
   2. Biosym IRG, Singapore-MIT Alliance for Research and Technology, Singapore, Singapore

   Contribution

   AP, Supervision, Investigation, Methodology, Writing—review and editing

   Competing interests

   The authors declare that no competing interests exist.

   "This ORCID iD identifies the author of this article:" 0000-0003-2777-1043

3. Marco Rasponi

   Department of Electronics, Information and Bioengineering, Politecnico di Milano, Milan, Italy

   Contribution

   MR, Supervision, Methodology, Writing—review and editing

   Competing interests

   The authors declare that no competing interests exist.

4. Gianfranco Beniamino Fiore

   Department of Electronics, Information and Bioengineering, Politecnico di Milano, Milan, Italy

   Contribution

   GBF, Supervision, Methodology, Writing—review and editing

   Competing interests

   The authors declare that no competing interests exist.

5. Roger Kamm

   1. Biosym IRG, Singapore-MIT Alliance for Research and Technology, Singapore, Singapore
   2. Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, United States

   Contribution

   RK, Supervision, Funding acquisition, Project administration, Writing—review and editing

   Competing interests

   The authors declare that no competing interests exist.

6. Monica Soncini

   Department of Electronics, Information and Bioengineering, Politecnico di Milano, Milan, Italy

   Contribution

   MS, Conceptualization, Supervision, Methodology, Funding acquisition, Project administration, Writing—review and editing

   For correspondence

   monica.soncini@polimi.it

   Competing interests

   The authors declare that no competing interests exist.

   "This ORCID iD identifies the author of this article:" 0000-0001-8607-7196

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