Bone marrow (BM) is the major site for hematopoiesis in adult life, and our knowledge of ILC development largely relies on studies of BM ILC progenitors (ILCPs). However, several lines of evidence show that progenitors with ILC potentials also exist in peripheral tissues. Our recent study shows that fetal and adult liver contain hematopoietic progenitors with the ability to generate liver-resident NK cells, which are also known as ILC1s. Besides ILC1s, ILC2s and ILC3s are also tissue-resident and not replaced by circulating hematopoietic cells, raising a possibility of a common BM-independent origin of tissue-resident ILCs.

Here, we show spatiotemporal dynamics of fetal liver (FL) and BM hematopoiesis progression to ILC subsets across tissues during ontogeny. ILC-restricted hematopoiesis is initiated in the fetal liver (FL) and then FL-derived PD-1+ ILC progenitors (ILCPs) seed fetal lung and intestine. Organ niches determine the commitment of ILCPs to downstream precursors, including bipotent ILC1-ILC3 precursors (ILC1/3Ps) that are preferentially residing in the liver and intestine and ILC2 precursors (ILC2Ps) that show predominance in the lung. These precursors persist in adulthood and contribute to local ILC pools via BM-independent manner. In contrast, intramedullary ILC2Ps and ILC2s rely on BM hematopoiesis. Thus, our study highlights extramedullary and intramedullary ILCs with different origins, providing a comprehensive framework for developmental dynamics of ILCs.