Dynamics of Human Prothymocytes and Xenogeneic Thymopoiesis in Hematopoietic Stem Cell-Engrafted Nonobese Diabetic-SCID/IL-2rγnull Mice

Abstract

To model the developmental pattern of human prothymocytes and thymopoiesis, we used NOD-scid/γc−/− mice grafted with human umbilical cord blood CD34+ hematopoietic progenitor cells (HPCs). Human prothymocytes developed in the murine bone marrow (BM) from multipotent CD34++CD38lolineage− HPCs to CD34++CD7+CD2- pro-T1 cells that progressed in a Notch-dependent manner to CD34+CD7++CD2+ pro-T2 cells, which migrated to the thymus. BM prothymocyte numbers peaked 1 mo after graft, dropped at mo 2, and persisted at low levels thereafter, with only a few CD34+CD7lo prothymocytes with limited T potential being detected by mo 5. As a consequence, thymopoiesis in this xenogeneic setting began by weeks 4–6, peaked at mo 3, and decreased thenceforth. Analyzing mice grafted at 2, 4 or 8, mo of age showed that in an “older” BM, prothymocyte differentiation was perturbed and resulted in CD34+CD7lo prothymocytes with limited T potential. Whereas the early drop in BM thymopoietic activity was related to a Notch-independent loss of T potential by CD34++CD38lolineage− HPCs, the later age-dependent production decline of prothymocytes was linked to a more complex mix of cell-intrinsic and microenvironmental defects. Accordingly, and contrasting with what was observed with umbilical cord blood HPCs, CD34+ HPCs from human adult BM displayed only marginal thymopoietic activity when grafted into young 2-mo-old NOD-scid/γc−/− mice. These data demonstrate that the developmental pattern of BM prothymocytes during human late fetal and early postnatal life can be reproduced in humanized mice, and they suggest that onset of human thymus involution relates to decreased colonization by prothymocytes.

Small-Molecule Inhibitor of Glycogen Synthase Kinase 3β 6-Bromoindirubin-3-oxime Inhibits Hematopoietic Regeneration in Stem Cell Recipient Mice

“…The peak of thymopoiesis was registered at week 5-12 post-transplant [13]. PB since the thymic function is reduced at late stages post-transplant due to thymic involution in aging mice [13]. Thus BIO given at late stages post-transplant does not attenuate T cell regeneration.…”

“…proportion of primitive CD34+ progenitor cells homed to the BM re-populates host thymus and gives rise to human T cells [13]. Human CD34+ progenitor cells acquire CD7 expression before losing CD34 expression and developing double positive CD4+CD8+ and single positive(SP) T cell subsets [13].…”

“…Human CD34+ progenitor cells acquire CD7 expression before losing CD34 expression and developing double positive CD4+CD8+ and single positive(SP) T cell subsets [13]. The peak of thymopoiesis was registered at week 5-12 post-transplant [13].…”

“…BIO given at later stages post-transplant still reduced human cell reconstitution in the BM but did not affect T cell counts in PB. It is relevant, that at late stages post-transplant, T cell balance in PB does not depend on thymopoiesis, but rather is associated with the homeostatic expansion of mature T cells [13].…”

The functional relationship between hematopoietic stem cells and developing T lymphocytes

“…However, in the NSG model, human T cells develop with all the developmental stages known from ex vivo human thyme. 51 In addition, Parietti et al were able to reproduce the development of human prothymocytes in the NSG xenograft model, 76 and it was demonstrated that human thymocytes can respond to murine MHC signals and have comparable migration on murine and human thymic slices. 77 Furthermore, for B cells, the xenogeneic environment shows a block identical to the block in development directly found in the Artemis-severe combined immunodeficiency (SCID) patient, and B cell development in controls was highly comparable to normal human BM.…”