Concise Review: Hematopoietic Stem Cell Transplantation: Targeting the Thymus

Abstract

Allogeneic hematopoietic stem cell (HSC) transplantation can cure patients suffering from diverse genetic and acquired diseases as well as cancers. Nevertheless, under conditions where T-cell reconstitution is critical, the entry of donor progenitors into the thymus remains a major bottleneck. It is assumed that following the intravenous injection of HSC, they first home to the BM. More committed progenitors can then be exported to the thymus in response to a myriad of signals regulating thymus seeding. Notably although, the thymus is not continually receptive to the import of hematopoietic progenitors. Furthermore, as stem cells with self-renewing capacity do not take up residence in the thymus under physiological conditions, the periodic colonization of the thymus is essential for the sustained differentiation of T lymphocytes. As such, we and others have invested significant efforts into exploring avenues that might foster a long-term thymus-autonomous differentiation. Here, we review strategic approaches that have resulted in long-term T-cell differentiation in immunodeficient (SCID) mice, even across histocompatibility barriers. These include the forced thymic entry of BM precursors by their direct intrathymic injection as well as the transplantation of neonatal thymi. The capacity of the thymus to support hematopoietic progenitors with renewal potential will hopefully promote the development of new therapeutic strategies aimed at enhancing T-cell differentiation in patients undergoing HSC transplantation.

Intrathymic adeno-associated virus gene transfer rapidly restores thymic function and long-term persistence of gene-corrected T cells

“…Consistent with the kinetics of thymocyte differentiation and emigration, 27,73,75,77 gene-corrected T cells were detected in the bloodstream within 3 weeks after intrathymic transfer (Fig 3, A). T cells were monitored in peripheral blood samples between 3 and 40 weeks after transduction.…”

“…Furthermore, mTEC turnover is estimated at 2 to 3 weeks, 71,72 suggesting that the decrease in AIRE 1 cell numbers that we observed at 10 weeks after gene transfer (Fig 2, B) was associated with a single wave of thymocyte differentiation. Indeed, within the WT thymus, percentages of gene-transduced cells that represented mature SP4 and SP8 thymocytes peaked at day 10 after gene transfer, likely representing maturation of DP thymocytes, 27,73,74 and decreased by 3 weeks, which is consistent with SP thymocyte emigration (P < .01; Figs 1, C, and 2, C). 75 Differentiation of SP4 and SP8 thymocytes was detected in AAV8-ZAP-70-treated ZAP-70 2/2 mice but was not associated with a significant change in total thymocyte numbers, likely because of similar initial thymocyte numbers in the WT and knockout (KO) mice (see Fig E1, B).…”

“…124,125 Furthermore, irradiation reduces progenitor homing by more than 10-fold. 29 Although this bottleneck can be partially overcome by injecting HSCs or hematopoietic progenitors directly into the thymus, 24,27,28,31,109,126,127 histocompatible donors are not always available. Our study reveals the potential of an intrathymic AAV8 gene therapy strategy to promote extremely rapid reconstitution of the thymus microenvironment and the differentiation of mTEC-dependent Treg cells within a 7-to 10-day period.…”

“…19 These HSCs, administered by means of intravenous injection, must continuously home to the thymus because under physiologic conditions, thymic settling progenitors are only able to give rise to a single round of thymocyte differentiation. [20][21][22][23] Notably, however, intrathymic injection of HSCs, as well as pro-T cells, improves T-cell differentiation in the thymus [24][25][26][27][28][29][30][31] and increases the expansion of supporting thymic epithelial cells (TECs). 32 Additionally, the thymus can be targeted through direct injection of antigens or vectors expressing genes of interest, [33][34][35][36][37] with recombinant adeno-associated virus (rAAV) vectors transducing thymocytes with a 10-fold greater efficiency than lentiviral vectors.…”

The Differentiation Balance of Bone Marrow Mesenchymal Stem Cells Is Crucial to Hematopoiesis

“…The process of T cell differentiation includes two stages: prethymic stage and thymic stage [ 38 ]. First, BM HSCs give rise to thymus-seeding progenitor of T cells, which migrate to thymus.…”