Highlights d A hPSC-derived cell and organoid platform is used to study SARS-CoV-2 tissue tropism d Human pancreatic alpha and beta cells are permissive to SARS-CoV-2 infection d Human hepatocyte and cholangiocyte organoids are permissive to SARS-CoV-2 infection d hPSC-derived cells/organoids show similar chemokine responses as COVID-19 tissues

Tissue homeostasis requires an effective, limited wound-healing response to injury. In chronic disease, failure to regenerate parenchymal tissue leads to the replacement of lost cellular mass with a fibrotic matrix. The mechanisms that dictate the balance of cell regeneration and fibrogenesis are not well understood 1 . Here we report that fibrogenic hepatic stellate cells (HSCs) in the liver are negative regulators of hepatocyte regeneration. This negative regulatory function requires stimulation of the 5-hydroxytryptamine 2B receptor (5-HT 2B ) on HSCs by serotonin, which activates expression of transforming growth factor β1 (TGF-β1), a powerful suppressor of hepatocyte proliferation, through signaling by mitogen-activated protein kinase 1 (ERK) and the transcription factor JunD. Selective antagonism of 5-HT 2B enhanced hepatocyte growth in models of acute and chronic liver injury. We also observed similar effects in mice lacking 5-HT 2B or JunD or upon selective depletion of HSCs in wild-type mice. Antagonism of 5-HT 2B attenuated fibrogenesis and improved liver function in disease models in which fibrosis was pre-established and progressive. Pharmacological targeting of 5-HT 2B is clinically safe in humans and may be therapeutic in chronic liver disease.

Abstract-By mimicking sympathetic stimulation in vivo, we previously reported that mice globally lacking serotonin 5-HT 2B receptors did not develop isoproterenol-induced left ventricular hypertrophy. However, the exact cardiac cell type(s) expressing 5-HT 2B receptors (cardiomyocytes versus noncardiomyocytes) involved in pathological heart hypertrophy was never addressed in vivo. We report here that mice expressing the 5-HT 2B receptor solely in cardiomyocytes, like global 5-HT 2B receptor-null mice, are resistant to isoproterenol-induced cardiac hypertrophy and dysfunction, as well as to isoproterenol-induced increases in cytokine plasma-levels. These data reveal a key role of noncardiomyocytes in isoproterenol-induced hypertrophy in vivo. Interestingly, we show that primary cultures of angiotensinogen null adult cardiac fibroblasts are releasing cytokines on stimulation with either angiotensin II or serotonin, but not in response to isoproterenol stimulation, demonstrating a critical role of angiotensinogen in adrenergic-dependent cytokine production. We then show a functional interdependence between AT 1 Rs and 5-HT 2B receptors in fibroblasts by revealing a transinhibition mechanism that may involve heterodimeric receptor complexes. Both serotonin-and angiotensin II-dependent cytokine production occur via a Src/heparin-binding epidermal growth factor-dependent transactivation of epidermal growth factor receptors in cardiac fibroblasts, supporting a common signaling pathway. Finally, we demonstrate that 5-HT 2B receptors are overexpressed in hearts from patients with congestive heart failure, this overexpression being positively correlated with cytokine and norepinephrine plasma levels. Collectively, these results reveal for the first time that interactions between AT 1 and 5-HT 2B receptors coexpressed by noncardiomyocytes are limiting key events in adrenergic agonist-induced, angiotensin-dependent cardiac hypertrophy. Accordingly, antagonists of 5-HT 2B receptors might represent novel therapeutics for sympathetic overstimulation-dependent heart failure. Key Words: fibroblast Ⅲ heart failure Ⅲ hypertrophy Ⅲ interleukins Ⅲ sympathetic nervous system C ardiac hypertrophy is a physiological adaptation of the heart to increased workload. Recent data challenged the widely held belief that cardiac hypertrophy is a necessary compensatory mechanism to maintain normal heart function. 1,2 When sustained and extensive, cardiac hypertrophy can lead to maladaptation and progressive dysfunction leading to heart failure secondary to cardiomyocyte apoptosis and fibrosis. 3 In addition to biomechanical stress, several neurohumoral factors acting via G protein-coupled receptors (GPCRs), including ␤-adrenergic (␤-AR), endothelin and angiotensin (Ang) II type 1 (AT 1 R) receptors have been identified as potent inducers of cardiac hypertrophy. 4 -7 The chronic adrenergic stimulation experienced by patients with congestive heart failure (CHF) is a strong predictor of morbidity and mortality. Norepinephrine, through stimulatio...