Modeling of human T cell developmentin vitroas a read-out for hematopoietic stem cell multipotency

Abstract

Hematopoietic stem cells (HSCs) reside in distinct sites throughout fetal and adult life and give rise to all cells of the hematopoietic system. Because of their multipotency, HSCs are capable of curing a wide variety of blood disorders through hematopoietic stem cell transplantation (HSCT). However, due to HSC heterogeneity, site-specific ontogeny and current limitations in generating and expanding HSCs in vitro, their broad use in clinical practice remains challenging. To assess HSC multipotency, evaluation of their capacity to generate T lymphocytes has been regarded as a valid read-out. Several in vitro models of T cell development have been established which are able to induce T-lineage differentiation from different hematopoietic precursors, although with variable efficiency. Here, we review the potential of human HSCs from various sources to generate T-lineage cells using these different models in order to address the use of both HSCs and T cell precursors in the clinic.

Transcriptional dynamics and epigenetic regulation of E and ID protein encoding genes during human T cell development

“…Combined with the largely overlapping ID1 / ID3 and ID2 / ID3 expression patterns during early and late human T cell development, respectively, and in the absence of any solid information on E-ID dimerization preferences, it is clear that functional studies with genetic approaches will be required to fully understand the specific roles of the E and ID proteins during human T cell development. Given the altered expression ratio of E/ID protein encoding genes during pre- and postnatal human T cell development, this will be required in both developmental windows and should be feasible now using CRISPR-mediated gene-editing tools in combination with the available in vitro models that support human T-lineage differentiation from various stem cell and hematopoietic precursor sources ( 16 , 107 , 108 ).…”

“…T cells develop in the thymus from multipotent lymphoid precursors. During this differentiation process, multiple decision checkpoints exist to generate the wide variety of conventional (αβ) and unconventional (γδ, CD8αα, MAIT, Treg and NK-T) T cells ( 15 , 16 ). First, bone marrow-derived progenitors gradually differentiate into immature T-lineage specified cells and eventually commit to the T cell fate, excluding potential for other lineages ( Figure 1A ).…”