Embryonic macrophages support endocrine commitment during human pancreatic differentiation

Organogenesis is a complex process that relies on a dynamic interplay between extrinsic factors originating from the microenvironment and tissue-specific intrinsic factors. For pancreatic endocrine cells, the local niche consists of acinar and ductal cells as well as neuronal, immune, endothelial, and stromal cells. Hematopoietic cells have been detected in human pancreas as early as 6 post-conception weeks, but whether they play a role during human endocrinogenesis remains unknown. To investigate this, we performed single-nucleus RNA sequencing (snRNA-seq) of the second-trimester human pancreas and identified a wide range of hematopoietic cells, including two distinct subsets of tissue-resident macrophages. Leveraging this discovery, we developed a co-culture system of human embryonic stem cell-derived endocrine-macrophage organoids to model their interaction in vitro. Here, we show that macrophages support the differentiation and viability of endocrine cells in vitro and enhance tissue engraftment, highlighting their potential role in tissue engineering strategies for diabetes. [Display omitted] •Characterization of the human fetal pancreatic microenvironment by snRNA-seq analysis•Identification of distinct fetal pancreatic tissue-resident macrophage populations•Modeling embryonic macrophage and endocrine crosstalk using hESC-derived co-culture•hESC-derived embryonic macrophages enhance endocrine differentiation and viability Using single-nucleus RNA sequencing (snRNA-seq), Migliorini et al. characterized the hematopoietic cells within the human fetal pancreatic microenvironment, uncovering distinct populations of tissue-resident macrophages. A co-culture system of hESC-derived organoids revealed that embryonic macrophages support endocrine cell differentiation, viability, and tissue engraftment, offering new avenues for future diabetes therapies.