In vitro and in vivo evaluation of possible pro-survival activities of PGE2, EGF, TPO and FLT3L on human hematopoiesis

Abstract

Myelosuppression is a major and frequently dose-limiting side effect of anticancer therapy and is responsible for most treatment-related morbidity and mortality. In addition, repeated cycles of DNA damage and cell death of hematopoietic stem and progenitor cells, followed by compensatory proliferation and selection pressure, lead to genomic instability and pave the way for therapy-related myelodysplastic syndromes and secondary acute myeloid leukemia. Protection of hematopoietic stem and progenitor cells from chemo- and radiotherapy in patients with solid tumors would reduce both immediate complications and long-term sequelae. Epidermal growth factor (EGF) and prostaglandin E2 (PGE2) were reported to prevent chemo- or radiotherapy-induced myelosuppression in mice. We tested both molecules for potentially protective effects on human CD34 + cells in vitro and established a xenograft mouse model to analyze stress resistance and regeneration of human hematopoiesis in vivo . EGF was neither able to protect human stem and progenitor cells in vitro nor to promote hematopoietic regeneration following sublethal irradiation in vivo . PGE2 significantly reduced in vitro apoptotic susceptibility of human CD34 + cells to taxol and etoposide. This could, however, be ascribed to reduced proliferation rather than to a change in apoptosis signaling and BCL-2 protein regulation. Accordingly, 16,16-dimethyl-PGE2 (dmPGE2) did not accelerate regeneration of the human hematopoietic system in vivo . Repeated treatment of sublethally irradiated xenograft mice with known antiapoptotic substances, such as human FLT3L and thrombopoietin (TPO), which suppress transcription of the proapoptotic BCL-2 proteins BIM and BMF, also only marginally promoted human hematopoietic regeneration in vivo .

BCL-XL expression is essential for human erythropoiesis and engraftment of hematopoietic stem cells

“…Since loss of human HSPC was not complete, it is very likely that other anti-apoptotic BCL-2 proteins, especially MCL-1, have an important role in HSPC survival 5,49 . Regarding the in vivo data, it should be kept in mind that xenograft models are of only limited feasibility in testing function and stress resistance of human stem cells 50 . Xenotransplantation comes along with incompatibility between human HSCs and the murine microenvironment, thereby imposing very high levels of stress on the transplanted cells.…”

A Retrospective Trial Exploring Erzhu Yiren Decoction in Gastric Ulcer with Spleen Deficiency and Dampness-Heat

“…The roasted Astragalus and stir-fried Atractylodes macrocephala Koidz in Erzhu Yiren Decoction invigorate the spleen and replenish Qi, and the stir-fried Squid Bone and Bletilla striata yield an excellent acid-inhibiting effect. Moreover, the combination with Lily with a moisturizing effect succeeds in replenishing Qi and invigorating the spleen, clearing away heat and dampness, and eventually yields a gastric-protective efficacy [26,27]. Therefore, the effective rate of gastroscopic ulcer healing in the observation group was significantly higher than that of the control group (P < 0:05), and the clinical symptom score after treatment was significantly lower than that of the control group (P < 0:001), indicating significantly improved gastric ulcer after the introduction of Erzhu Yiren Decoction.…”

Establishment of a Novel CD34+ Hematopoietic Stem Cell-Derived Xenograft Model of Hyperleukocytic Acute Myeloid Leukemia

“…According to previous reports, 1.5-3.5 Gy doses of χ-ray radiation have been used before leukemia cell [18][19][20] or CD34 + cells [21,22] transplantation into mice, but only a few studies did not use irradiation [23]; for example, Shafat et al reported the successful construction of a primary AML model with nonirradiated NSG mice [24]. In this study, we explored the radiation dose in model construction.…”