Delineating spatiotemporal and hierarchical development of human fetal innate lymphoid cells

Abstract

Whereas the critical roles of innate lymphoid cells (ILCs) in adult are increasingly appreciated, their developmental hierarchy in early human fetus remains largely elusive. In this study, we sorted human hematopoietic stem/progenitor cells, lymphoid progenitors, putative ILC progenitor/precursors and mature ILCs in the fetal hematopoietic, lymphoid and non-lymphoid tissues, from 8 to 12 post-conception weeks, for single-cell RNA-sequencing, followed by computational analysis and functional validation at bulk and single-cell levels. We delineated the early phase of ILC lineage commitment from hematopoietic stem/progenitor cells, which mainly occurred in fetal liver and intestine. We further unveiled interleukin-3 receptor as a surface marker for the lymphoid progenitors in fetal liver with T, B, ILC and myeloid potentials, while IL-3RA– lymphoid progenitors were predominantly B-lineage committed. Notably, we determined the heterogeneity and tissue distribution of each ILC subpopulation, revealing the proliferating characteristics shared by the precursors of each ILC subtype. Additionally, a novel unconventional ILC2 subpopulation (CRTH2– CCR9+ ILC2) was identified in fetal thymus. Taken together, our study illuminates the precise cellular and molecular features underlying the stepwise formation of human fetal ILC hierarchy with remarkable spatiotemporal heterogeneity.

Building early defenses

“…The authors further assessed the in vitro lineage potential of Lin -CD34 + CD127 + IL3RA + cells (which should include some LP1 and LP2 progenitor populations) and compared their lineage potential in vitro with ILCPs from fetal liver. 8 As expected, fetal ILCPs gave rise to all helper ILC subsets. Newly identified IL3RA + progenitors possessed lineage potential for NK cells, myeloid cells but very limited potential for B cells.…”

“…In a study published in Cell Research, Liu et al used single-cell RNA sequencing (scRNA-seq) and flow cytometry to analyze ILCs and Lin -CD34 + progenitors in human fetal tissues including liver, intestine, thymus, spleen, skin and lung from 8 to 12 postconception weeks (PCW). 8 They found the major helper ILC subset was ILC3 in all tissues. Frequencies of ILC2s and putative ILC1s were highest in thymus, and the frequency of helper ILCs in thymus was greatly reduced from 8 to 12 PCW.…”

“…Liu et al further characterized the heterogeneity of each group of ILCs in different tissues by scRNA-seq analysis. 8 They found a putative precursor subset in each group of ILCs (pre-ILCs) by high expression of cell cycle genes and low expression of ILC lineage genes, which could correspond to a committed precursor stage of each group of ILCs. Pre-ILC3s are likely to be LTi precursors since LTi cells are the major subset of group 3 ILCs at fetal stage in mouse.…”

“…9 Liu et al compared expression levels of transcription factors related with ILC development in ILCPs and pre-ILCs. 8 The transcription factor TCF-1 is highly expressed in ILC progenitors in mouse and required for mouse ILCP development. 4 Interestingly, the authors found that TCF-1 was poorly expressed in human fetal ILCPs, suggesting that TCF-1 may not be critical for human fetal ILCP development.…”

China's top 10 hematological advances in 2021 lists the key developments in hematology in China for that year

“…Bing Liu's team used single-cell RNA sequencing and functional validation to explore the ILC development in human fetal tissues. 7 The development trajectory from hematopoietic stem and progenitor cells, through two stages of lymphoid progenitors, to ILC progenitor in fetal liver is revealed, followed by the specification and mature stages to generate three sub-groups of ILC in lymphoid and nonlymphoid tissues. Intriguingly, the novel lymphoid progenitors were characterized by expression of IL-3RA undergoing ILC lineage specification in fetal liver.…”