Stem Cell Factor Consistently Improves Thymopoiesis after Experimental Transplantation of Murine or Human Hematopoietic Stem Cells in Immunodeficient Mice

Abstract

Deficient thymopoiesis is a pivotal determinant of impaired immune competence following hematopoietic stem cell transplantation (HSCT). Stem cell factor (SCF) is essentially involved in early thymopoiesis. We evaluated whether SCF administration would improve recovery of thymopoiesis following HSCT in immunodeficient mice receiving: 1) bone marrow (BM) transplantation of congenic mice; or 2) human fetal liver HSCT in the human immune system mouse model. Following murine BM transplantation, SCF significantly enhanced thymopoiesis and peripheral T cell recovery in lymph nodes and spleen. SCF did not affect BM lymphoid progenitor recovery and/or expansion. Median thymic cellularity increased from 0.9 in PBS- to 266 × 104/thymus in SCF-treated mice (p = 0.05). Following human HSCT in human immune system mice, higher thymic cellularity was observed in SCF-treated mice. Double-negative and early double-positive thymocyte subsets increased, but especially late double-positive, CD4 single-positive, and CD8 single-positive thymocyte subsets were significantly enhanced (p < 0.05). These results show that exogenous supply of SCF may significantly improve murine and human posttransplant thymopoiesis, for which the effect is probably exerted by directly promoting T cell development intrathymically rather than by enhanced entry of prethymically expanded lymphoid progenitors.

Effective Elicitation of Human Effector CD8+ T Cells in HLA-B*51:01 Transgenic Humanized Mice after Infection with HIV-1

“…Therefore, the frequency of human T cell reconstitution in the hNOK/B51Tg mice was lower than that for humanized NSG mice [6] . Recent studies showed that the frequency of human cell reconstitution in human transgenic membrane-bound stem cell factor (SCF) NSG mice (NSG-Tg (hu-mSCF)) is higher than that in irradiated NSG mice [53] and that SCF administration improves the recovery of thymopoiesis following HSC transplantation in Rag2 −/− γC −/− mice [54] . These findings suggest that SCF administration to hNOK/B51Tg mice may enhance human HSC engraftment and T cell reconstitution in these mice.…”

IL-7 and SCF Levels Inversely Correlate with T Cell Reconstitution and Clinical Outcomes after Cord Blood Transplantation in Adults

“…The SCF/c-kit axis is essential in the earliest stages of thymopoeisis [ 20 , 22 – 24 ]. In a murine model of transplantation, it has been shown that SCF administration improves post-transplant thymopoiesis largely by promoting intrathymic T cell development, rather than by enhancing entry of prethymically expanded lymphoid progenitors [ 25 ]. A synergistic effect of SCF with IL-7 in the improvement of murine thymopoiesis has also been reported [ 26 ].…”

Keratinocyte Growth Factor and Stem Cell Factor to Improve Thymopoiesis after Autologous CD34+ Cell Transplantation in Rhesus Macaques

“…Further preclinical studies are needed in order to develop a better tolerable therapeutic protocol that may possibly be evaluated clinically. Given the direct stimulatory capacity of SCF alone on human thymopoiesis, as recently demonstrated in a humanized mouse model [31], further study of the combination of KGF and low-dose SCF may still be warranted. Alternatively, continuous rather than bolus dosing may be an appropriate method to limit SCF toxicity without losing beneficial effects on thymopoiesis [52].…”

“…Administration of SCF in mice accelerated leukocyte recovery following radiation-induced myeloablation [28] but not following 5-fluorouracil (5-FU) treatment [29] or myeloablative HSCT [30]. Recently, we showed that SCF administration improved thymopoiesis in a humanized mice model [31]. In the present study, we evaluated the effect of KGF alone or combined with SCF on T cell reconstitution and thymopoiesis following myeloablative autologous HSCT into rhesus macaques.…”