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

Highlights d FACS of NURR1::GFP dopaminergic (DA) precursors enriches DA neuron culture purity d SATB1 KO DA neurons show hallmarks of cellular senescence, including SASP d SATB1 is required to repress CDKN1A in DA neurons d Senescence induced by SATB1 reduction in vivo induces microglial activation

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In Parkinson's disease (PD), there are currently no effective therapies to prevent or slow down disease progression. Cell replacement therapy using human pluripotent stem cell (hPSC)-derived dopamine neurons holds considerable promise. It presents a novel, regenerative strategy, building on the extensive history of fetal tissue grafts and capturing the potential of hPSCs to serve as a scalable and standardized cell source. Progress in establishing protocols for the direct differentiation to midbrain dopamine (mDA) neurons from hPSC have catalyzed the development of cell-based therapies for PD. Consequently, several groups have derived clinical-grade mDA neuron precursors under clinical good manufacture practice condition, which are progressing toward clinical testing in PD patients. Here we will review the current status of the field, discuss the remaining key challenges, and highlight future areas for further improvements of hPSC-based technologies in the clinical translation to PD.

ATP citrate lyase (ACLY) is a key enzyme that is involved in de novo lipogenesis by catalyzing conversion of cytosolic citrate into acetyl CoA and oxaloacetate. Up-regulation of ACLY in various types of tumors enhances fatty acid synthesis and supplies excess acetyl CoA for histone acetylation. However, there is evidence that its enzymatic activity alone is insufficient to explain ACLY silencing-mediated growth arrest in tumor cells. In this study, we found that ACLY knockdown in primary human cells triggers cellular senescence and activation of tumor suppressor p53. Provision of acetyl CoA to ACLY knockdown cells did not alleviate ACLY silencinginduced p53 activation, suggesting an independent role for ACLY activity. Instead, ACLY physically interacted with the catalytic subunit of AMPactivated protein kinase (AMPK) and inhibited AMPK activity. The activation of AMPK under ACLY knockdown conditions may lead to p53 activation, ultimately leading to cellular senescence. In cancer cells, ACLY silencing-induced p53 activation facilitated DNA damage-induced cell death. Taken together, our results suggest a novel function of ACLY in cellular senescence and tumorigenesis.