T lymphocyte potential marks the emergence of definitive hematopoietic progenitors in human pluripotent stem cell differentiation cultures.

The efficient generation of hematopoietic stem cells from human pluripotent stem cells is dependent on the appropriate specification of the definitive hematopoietic program during differentiation. In this study, we used T lymphocyte potential to track the onset of definitive hematopoiesis from human embryonic and induced pluripotent stem cells differentiated with specific morphogens in serum- and stromal-free cultures. We show that this program develops from a progenitor population with characteristics of hemogenic endothelium, including the expression of CD34, VE-cadherin, GATA2, LMO2, and RUNX1. Along with T cells, these progenitors display the capacity to generate myeloid and erythroid cells. Manipulation of Activin/Nodal signaling during early stages of differentiation revealed that development of the definitive hematopoietic progenitor population is not dependent on this pathway, distinguishing it from primitive hematopoiesis. Collectively, these findings demonstrate that it is possible to generate T lymphoid progenitors from pluripotent stem cells and that this lineage develops from a population whose emergence marks the onset of human definitive hematopoiesis.

Key players for T-cell regeneration.

PURPOSE OF REVIEW: The thymus provides a unique and essential microenvironment for T-cell precursors to develop into mature functionally competent T lymphocytes. Ageing causes architectural changes in the thymus resulting in a loss of thymic epithelial space required for thymopoiesis - a process known as thymic involution. Additionally, cytoablative regimens used to treat malignancies also destroy thymic architecture. The net result of both processes is diminished thymic output and function that may lead to impaired immunity. Thus, immunocompromised individuals would benefit from strategies aimed at enhancing T-cell reconstitution. RECENT FINDINGS: Here we discuss strategies such as the use of sex steroid ablation, keratinocyte growth factor, interleukin-7, and in-vitro-generated progenitor T cells as candidates for restoring T-cell immunity. Using various animal models of ageing or hematopoietic stem cell transplantation, these strategies have been shown to restore thymic architecture and cellularity, resulting in increased output and T-cell function in the periphery. SUMMARY: These candidate approaches are currently being tested in clinical trials, with preliminary evidence showing encouraging effects on T-cell reconstitution. Nevertheless, although these strategies show clear promise in animal models, and in early human trials, further data are needed to determine their efficacy in patients.