Generating human artery and vein cells from pluripotent stem cells highlights the arterial tropism of Nipah and Hendra viruses.
Stem cell research endeavors to generate specific subtypes of classically defined "cell types." Here, we generate >90% pure human artery or vein endothelial cells from pluripotent stem cells within 3-4 days. We specified artery cells by inhibiting vein-specifying signals and vice versa. These cells modeled viral infection of human vasculature by Nipah and Hendra viruses, which are extraordinarily deadly (∼57%-59% fatality rate) and require biosafety-level-4 containment. Generating pure populations of artery and vein cells highlighted that Nipah and Hendra viruses preferentially infected arteries; arteries expressed higher levels of their viral-entry receptor. Virally infected artery cells fused into syncytia containing up to 23 nuclei, which rapidly died. Despite infecting arteries and occupying ∼6%-17% of their transcriptome, Nipah and Hendra largely eluded innate immune detection, minimally eliciting interferon signaling. We thus efficiently generate artery and vein cells, introduce stem-cell-based toolkits for biosafety-level-4 virology, and explore the arterial tropism and cellular effects of Nipah and Hendra viruses.
View details for DOI 10.1016/j.cell.2022.05.024
View details for PubMedID 35738284
Controversies surrounding the origin of hepatocytes in adult livers and the in vitro generation or propagation of hepatocytes.
Cellular and molecular gastroenterology and hepatology
Epithelial cells in the liver (known as hepatocytes) are high-performance engines of myriad metabolic functions and versatile responders to liver injury. As hepatocytes metabolize amino acids, alcohol, drugs and other substrates, they produce and are exposed to a milieu of toxins and harmful byproducts that can damage themselves. In the healthy liver, hepatocytes generally divide slowly. However, after liver injury, hepatocytes can ramp up proliferation to regenerate the liver. Yet, upon extensive injury, regeneration falters and liver failure ensues. It is therefore critical to understand the mechanisms underlying liver regeneration, and in particular, which liver cells are mobilized during liver maintenance and repair. Controversies continue to surround the very existence of hepatic stem cells and, if they exist, their spatial location, multipotency, degree of contribution to regeneration, ploidy, and susceptibility to tumorigenesis. This review discuss these controversies. Finally, we highlight how insights into hepatocyte regeneration and biology in vivo can inform in vitro studies to propagate primary hepatocytes with signals in liver regeneration and to generate hepatocytes de novo from pluripotent stem cells.
View details for DOI 10.1016/j.jcmgh.2020.09.016
View details for PubMedID 32992051
Circulating tumor cells exhibit metastatic tropism and reveal brain metastasis drivers.
Hematogenous metastasis is initiated by a subset of circulating tumor cells (CTCs) shed from primary or metastatic tumors into the blood circulation. Thus, CTCs provide a unique patient biopsy resource to decipher the cellular subpopulations that initiate metastasis and their molecular properties. However, one crucial question is whether CTCs derived and expanded ex vivo from patients recapitulate human metastatic disease in an animal model. Here, we show that CTC lines established from breast cancer patients are capable of generating metastases in mice with a pattern recapitulating most major organs from corresponding patients. Genome-wide sequencing analyses of metastatic variants identified semaphorin 4D (SEMA4D) as a regulator of tumor cell transmigration through the blood-brain-barrier and MYC as a crucial regulator for the adaptation of disseminated tumor cells to the activated brain microenvironment. These data provide the direct experimental evidence of the promising role of CTCs as a prognostic factor for site-specific metastasis.
View details for DOI 10.1158/2159-8290.CD-19-0384
View details for PubMedID 31601552