来源于肠道组织的上皮器官（称为“enteroids”）在体外重现了器官的许多方面，可用于生物发现、个性化医学和药物开发。我们在此检查了人类肠道发育过程中的细胞信号环境，以确定可能对上皮细胞发育和稳态至关重要的生长环境信号。我们发现，一种EGF家族成员——EPIREGULIN（EREG）在人类发育中的隐窝内得到强烈表达。在含有EGF的标准培养条件下生长的人类发育肠道所生成的enteroids，主要由干细胞和祖细胞组成，几乎没有分化和空间组织。我们的研究表明EREG能在体外取代EGF，EREG会形成具有分化腺囊和增殖区域以及分化了的中央空腔的空间分辨enteroids。对原始隐窝、EGF生长和EREG生长的enteroids进行多组学（转录组和表观基因组）分析表明，EGF-enteroids具有依赖于EGF浓度的改变染色质景观，下调主要肠道转录因子CDX2，并畸变表达胃部基因的现象。这与EREG生长的enteroids相反，后者在培养中仍保持肠道的特点。因此，EREG能够在体外创造一个稳态的肠道生长环境，实现对干细胞功能、细胞分化和疾病建模的研究。

Epithelial organoids derived from intestinal tissue, called 'enteroids', recapitulate many aspects of the organ in vitro, and can be used for biological discovery, personalized medicine, and drug development. Here, we interrogated the cell signaling environment within the developing human intestine to identify niche cues that may be important for epithelial development and homeostasis. We identify an EGF family member, EPIREGULIN (EREG), which is robustly expressed in the developing human crypt. Enteroids generated from the developing human intestine grown in standard culture conditions, which contain EGF, are dominated by stem and progenitor cells, feature little differentiation and no spatial organization. Our results demonstrate that EREG can replace EGF in vitro, and EREG leads to spatially resolved enteroids that feature budded and proliferative crypt domains and a differentiated villus-like central lumen. Multiomic (transcriptome plus epigenome) profiling of native crypts, EGF-grown and EREG-grown enteroids show that EGF-enteroids have an altered chromatin landscape that is dependent on EGF concentration, downregulate the master intestinal transcription factor CDX2, and ectopically express stomach genes, a phenomenon that is reversible. This is in contrast to EREG-grown enteroids, which remain intestine-like in culture. Thus, EREG creates a homeostatic intestinal niche in vitro, enabling interrogation of stem cell function, cellular differentiation, and disease modeling.