{
  "abstract": "Introduction Cardiac involvement occurs in up to 45% of patients with SSc and is associated with an approximately fivefold increase in mortality. Principal manifestations include myocardial fibrosis and arrhythmias. Cardiac involvement is notoriously hard to study due to lack of human samples, particularly from early disease states, necessitating the use of in vitro models such as microtissues. Therapeutic options remain limited: vasodilators such as calcium-channel blockers may improve perfusion and contractility, yet high-quality randomized evidence is lacking.Numerous studies have shown that the liver is a hub of immunometabolic control and releases cytokines, hepatokines, and metabolites that modulate systemic inflammation. Several liver-derived factors have been implicated in antifibrotic and cardioprotective signaling, suggesting that hepatic outputs can shape myocardial remodeling. On this basis, we hypothesized that liver-mediated signaling influences profibrotic responses in the heart.Material and Methods We generated scaffold-free cardiac microtissues (cMTs) from human induced pluripotent stem cell-derived cardiomyocytes and human fetal cardiac fibroblasts. Scaffold-free liver microtissues (lMTs) comprising primary hepatocytes, endothelial cells, and Kupffer cells were co-cultured with cMTs on the Akura Twin Plate. The plate connects paired wells via a microchannel and is continuously tilted to induce bidirectional flow. Two variants were studied: cardiac-only (CO-MTs) and cardiac-liver (CL-MTs), each with or without TGF-beta stimulation. Outcomes included contractility (live imaging with MUSCLEMOTION), viability (caspase-3/7), liver function (ALT), secreted proteins (ELISA), and extracellular matrix deposition (immunohistochemistry).Results CL-MTs exhibited a significantly lower beating rate, longer contraction duration, time-to-peak, and relaxation time than CO-MTs (n=88-94) with and without TGF-beta stimulation. In both CO-MTs and CL-MTs, TGF-beta reduced beating rate and prolonged contraction duration, time-to-peak, and relaxation time. Procollagen type I alpha-1 (Pro-Col1a1) secretion was increased in fibrotic CO-MTs versus non-fibrotic CO-MTs, whereas CL-MTs did not respond to TGF-beta and displayed comparable Pro-Col1a1 in fibrotic and non-fibrotic conditions (n=22-24). Alpha-smooth muscle actin and periostin increased with TGF-beta in both CO-MTs and CL-MTs (n=11-26). Apoptosis (n=14-18) and ALT activity (n=9-19) did not differ significantly between variants with or without TGF-beta stimulation.Conclusions Cardiac-liver co-culture reduced TGF-beta-induced fibrotic remodeling in cMTs, evidenced by lower Pro-Col1a1 secretion. Viability and hepatic function were preserved. These data implicate protective hepatic paracrine signaling, which may limit cardiac fibrosis and may help explain heterogeneity in SSc cardiac involvement. Identifying the responsible hepatic factors could guide therapies that exploit liver-heart crosstalk to prevent or treat SSc-associated cardiomyopathy.",
  "authors": [
    {
      "affiliations": [
        "Center of Experimental Rheumatology, Department of Rheumatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland"
      ],
      "name": "Lukas Minder"
    },
    {
      "affiliations": [
        "Center of Experimental Rheumatology, Department of Rheumatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland"
      ],
      "name": "Astrid Hofman"
    },
    {
      "affiliations": [
        "Center of Experimental Rheumatology, Department of Rheumatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland"
      ],
      "name": "Ellen Kossmann"
    },
    {
      "affiliations": [
        "Center of Experimental Rheumatology, Department of Rheumatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland"
      ],
      "name": "Amela Hukara"
    },
    {
      "affiliations": [
        "Center of Experimental Rheumatology, Department of Rheumatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland"
      ],
      "name": "Ievgeniia Kocherova"
    },
    {
      "affiliations": [
        "Center of Experimental Rheumatology, Department of Rheumatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland"
      ],
      "name": "Andrea Laimbacher"
    },
    {
      "affiliations": [
        "InSphero AG, Schlieren, Switzerland"
      ],
      "name": "Lisa Hölting"
    },
    {
      "affiliations": [
        "InSphero AG, Schlieren, Switzerland"
      ],
      "name": "Tamara Häfeli"
    },
    {
      "affiliations": [
        "Center of Experimental Rheumatology, Department of Rheumatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland"
      ],
      "name": "Oliver Distler"
    },
    {
      "affiliations": [
        "Center of Experimental Rheumatology, Department of Rheumatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland"
      ],
      "name": "Przemyslaw Blyszczuk"
    },
    {
      "affiliations": [
        "Center of Experimental Rheumatology, Department of Rheumatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland"
      ],
      "name": "Gabriela Kania"
    }
  ],
  "title": "P.155 The liver’s impact on cardiac fibrosis in a liver-cardiac multi-organ-on-a-chip system",
  "uid": "3aecc9bd-60af-5968-b6d5-d45264723897"
}