Lymphoid cell development from fetal hematopoietic progenitors and human pluripotent stem cells

Abstract

The lymphoid hematopoietic lineage gives rise to a broad spectrum of immune cell types, including T cells, B cells, and natural killer (NK) cells as a subtype of innate lymphoid cells (ILCs). These cell types are thought to arise from long-term hematopoietic stem cells (HSCs) that reside in the adult bone marrow (BM), later maturing in primary lymphoid organs, namely the thymus and the BM. Following lymphoid commitment, hematopoietic progenitors differentiate to functional T and B cells through a process that incorporates DNA recombination events that generate antigen-specific receptors. In this context, a hallmark of adaptive immune cell development is the expression of the RAG genes (RAG1 and RAG2), encoding proteins that mediate

Divergent molecular events underlying initial T-cell commitment in human prenatal and postnatal thymus

“…However, the study of T-cell development especially during human embryogenesis has been dampened due to the scarcity of fetal material available and lack of appropriate techniques. Knowledge on early human embryonic T lymphopoiesis is vital for understanding physiology and pathological conditions and for developing immunotherapies ( 50 ). Recent advances in scRNA-seq technique have provided important new insights into the heterogeneity of T-cell precursors and the molecular mechanisms underlying T-cell lineage commitment at the single-cell level.…”

Developmental Programming of the Fetal Immune System by Maternal Western-Style Diet: Mechanisms and Implications for Disease Pathways in the Offspring

“…In addition to myeloid cells, common lymphoid progenitor cells go through a series of developments outside of the bone marrow during the maturation of a fetus [ 23 ]. Lymphoid cells are a diverse group of immune cells, from the adaptive responses of T and B cells to their innate partners, including natural killer (NK) cells and innate lymphoid cells.…”

Layered immune system development in mice and humans

“…Until it is possible to do so, whether these cells emerge in distinct waves, if at all, in humans remains to be determined. Sun et al 25 discuss the difficulty in definitively fate‐mapping lymphoid cells in humans back to their developmental origin. As a result, they point out that, despite suggestive literature, it is difficult to conclude that human yolk sac progenitors give rise to lymphocytes in an HSC independent manner as has been shown in mice.…”

“…In addition, they point out that the sophisticated lineage tracing models that have been used in mice, discussed in the various chapters herein and the review from Van de Parvet 15 in particular, are not available. That is why various in vitro models, including the generation of HSCs and progenitors from embryonic or induced pluripotent stem cells and systems such as the artificial thymus organ (ATO) cultures 26,27 will be important for defining the developmental potential of fetal and adult derived stem and progenitor cells as further discussed by Sun et al 25 . The ATO model is a particularly powerful system as it generates the full range of human T differentiation, including production of mature CD4 + and CD8 + T cells, and allows comparisons of development from fetal and adult hematopoietic stem and progenitor cells (HSPCs).…”

“…That is why various in vitro models, including the generation of HSCs and progenitors from embryonic or induced pluripotent stem cells and systems such as the artificial thymus organ (ATO) cultures 26,27 will be important for defining the developmental potential of fetal and adult derived stem and progenitor cells as further discussed by Sun et al. 25 The ATO model is a particularly powerful system as it generates the full range of human T differentiation, including production of mature CD4 + and CD8 + T cells, and allows comparisons of development from fetal and adult hematopoietic stem and progenitor cells (HSPCs). For example, in contrast to postnatal thymopoiesis, terminal deoxynucleotidyl transferase (TdT) expression is absent during T cell differentiation from pluripotent stem cells in ATOs, reflecting a previously reported property of fetal lymphopoiesis.…”