Human liver sinusoidal endothelial cells support the development of functional human pluripotent stem cell-derived Kupffer cells.

In mice, the first liver-resident macrophages, known as Kupffer cells (KCs), are thought to derive from yolk sac (YS) hematopoietic progenitors that are specified prior to the emergence of the hematopoietic stem cell (HSC). To investigate human KC development, we recapitulated YS-like hematopoiesis from human pluripotent stem cells (hPSCs) and transplanted derivative macrophage progenitors into NSG mice previously humanized with hPSC-liver sinusoidal endothelial cells (LSECs). We demonstrate that hPSC-LSECs facilitate stable hPSC-YS-macrophage engraftment for at least 7 weeks. Single-cell RNA sequencing (scRNA-seq) of engrafted YS-macrophages revealed a homogeneous MARCO-expressing KC gene signature and low expression of monocyte-like macrophage genes. In contrast, human cord blood (CB)-derived macrophage progenitors generated grafts that contain multiple hematopoietic lineages in addition to KCs. Functional analyses showed that the engrafted KCs actively perform phagocytosis and erythrophagocytosis in vivo. Taken together, these findings demonstrate that it is possible to generate human KCs from hPSC-derived, YS-like progenitors.

ΔNp63-restricted viral mimicry response impedes cancer cell viability and remodels tumor microenvironment in esophageal squamous cell carcinoma.

Tumor protein p63 isoform ΔNp63 plays roles in the squamous epithelium and squamous cell carcinomas (SCCs), including esophageal SCC (ESCC). By integrating data from cell lines and our latest patient-derived organoid cultures, derived xenograft models, and clinical sample transcriptomic analyses, we identified a novel and robust oncogenic role of ΔNp63 in ESCC. We showed that ΔNp63 maintains the repression of cancer cell endogenous retrotransposon expression and cellular double-stranded RNA sensing. These subsequently lead to a restricted cancer cell viral mimicry response and suppressed induction of tumor-suppressive type I interferon (IFN-I) signaling through the regulations of Signal transducer and activator of transcription 1, Interferon regulatory factor 1, and cGAS-STING pathway. The cancer cell ΔNp63/IFN-I signaling axis affects both the cancer cell and tumor-infiltrating immune cell (TIIC) compartments. In cancer cells, depletion of ΔNp63 resulted in reduced cell viability. ΔNp63 expression is negatively associated with the anticancer responses to viral mimicry booster treatments targeting cancer cells. In the tumor microenvironment, cancer cell TP63 expression negatively correlates with multiple TIIC signatures in ESCC clinical samples. ΔNp63 depletion leads to increased cancer cell antigen presentation molecule expression and enhanced recruitment and reprogramming of tumor-infiltrating myeloid cells. Similar IFN-I signaling and TIIC signature association with ΔNp63 were also observed in lung SCC. These results support the potential application of ΔNp63 as a therapeutic target and a biomarker to guide candidate anticancer treatments exploring viral mimicry responses.

From struggle to strength in African and Middle Eastern newcomers' integration stories to Canada: A participatory health equity research study.

BACKGROUND AND OBJECTIVES: Newcomers (immigrants, refugees, and international students) face many personal, gender, cultural, environmental and health system barriers when integrating into a new society. These struggles can affect their health and social care, reducing access to mental health care. This study explores the lived experiences of African and Middle Eastern newcomers to Ontario, Canada. An understanding of newcomer integration challenges, successes and social justice issues is needed to improve health equity and social services. METHODS: In this qualitative study, we used a participatory research approach to collect stories reflecting participants' integration perspectives and experiences. Beginning with our immigrant community network, we used snowball sampling to recruit newcomers, ages 18 to 30, originating from Africa or the Middle East. We used qualitative narrative analysis to interpret stories, identifying context themes, integrating related barriers and facilitators, and resolutions and learnings. We shared our findings and sought final feedback from our participants. FINDINGS: A total of 18 newcomers, 78% female and approximately half post-secondary students, participated in the study. Participants described an unknown and intimidating migration context, with periods of loneliness and isolation aggravated by cold winter conditions and unfamiliar language and culture. Amidst the struggles, the support of friends and family, along with engaging in schoolwork, exploring new learning opportunities, and participating in community services, all facilitated integration and forged new resilience. CONCLUSIONS: Community building, friendships, and local services emerged as key elements for future immigrant service research. Utilizing a participatory health research approach allowed us to respond to the call for social justice-oriented research that helps to generate scientific knowledge for promoting culturally adaptive health care and access for marginalized populations.