Balamurugan, A. | bioRxiv Science

bioRxiv2024

Fetal Liver-like Organoids Recapitulate Blood-Liver Niche Development and Multipotent Hematopoiesis from Human Pluripotent Stem Cells

The fetal liver is a hematopoietic organ, hosting a diverse and evolving progenitor population. While human liver organoids derived from pluripotent stem cells (PSCs) mimic aspects of embryonic and fetal development, they typically lack the complex hematopoietic niche and the interaction between hepatic and hematopoietic development. We describe the generation of human Fetal Liver-like Organoids (FLOs), that model human hepato-hematopoietic interactions previously characterized in mouse models. Developing FLOs first integrate a yolk sac-like hemogenic endothelium into hepatic endoderm and mesoderm specification. As the hepatic and hematopoietic lineages differentiate, the FLO culture model establishes an autonomous niche capable of driving subsequent progenitor differentiation without exogenous factors. Consistent with yolk sac-derived waves, hematopoietic progenitor cells (HPCs) within FLOs exhibit multipotency with a preference for myeloid lineage commitment, while retaining fetal B and T cell differentiation potential. We reconstruct in FLOs the embryonic monocyte-to-macrophage and granulocyte immune trajectories within the FLO microenvironment and assess their functional responses in the liver niche. In vivo, FLOs demonstrate a liver engraftment bias of hematopoietic cells, recapitulating a key phenomenon of human hematopoietic ontogeny. Our findings highlight the intrinsic capacity of liver organoids to support hematopoietic development, establishing FLOs as a platform for modeling and manipulating human blood-liver niche interactions during critical stages of development and disease.

developmental biology↗

bioRxiv2019

Myt Transcription Factors prevent stress-response gene over-activation to enable postnatal pancreatic β cell proliferation and function

Although stress response maintains cell function and survival under adverse conditions, over-activation of late-stage stress-gene effectors causes dysfunction and death. Here we show that the Myelin Transcription Factors (Myt 1, 2, and 3 TFs) prevent this over-activation. Co-inactivating Myt TFs in mouse pancreatic progenitors compromised postnatal {beta}-cell function, proliferation, and survival, preceded by upregulation of late-stage stress-response genes Activating Transcription Factors (e.g., Atf4) and Heat Shock Proteins (Hsps). Myt1 binds the putative enhancers of Atf4 and Hsps, whose over-expression in mouse {beta} cells largely recapitulated the Myt mutant phenotypes. Moreover, Myt(MYT)-TF levels were upregulated in functional mouse and human {beta} cells by metabolic stress but downregulated in those of type 2 diabetic islets that display ATF4 and HSP over-activation. Lastly, human MYT knockdown caused stress-gene over-activation and death in Endo-{beta}H1 cells. These findings suggest that the Myt TFs restrict stress-response to physiologically tolerable levels in mice and human.

developmental biology↗