Endothelial selectins and vascular cell adhesion molecule-1 promote hematopoietic progenitor homing to bone marrow - PubMed (original) (raw)

Endothelial selectins and vascular cell adhesion molecule-1 promote hematopoietic progenitor homing to bone marrow

P S Frenette et al. Proc Natl Acad Sci U S A. 1998.

Abstract

The adhesive mechanisms allowing hematopoietic progenitor cells (HPC) homing to the bone marrow (BM) after BM transplantation are poorly understood. We investigated the role of endothelial selectins and vascular cell adhesion molecule-1 (VCAM-1) in this process. Lethally irradiated recipient mice deficient in both P-and E-selectins (P/E-/-), reconstituted with minimal numbers (</=5 x 10(4)) of wild-type BM cells, poorly survived the procedure compared with wild-type recipients. Excess mortality in P/E-/- mice, after a lethal dose of irradiation, was likely caused by a defect of HPC homing. Indeed, we observed that the recruitment of HPC to the BM was reduced in P/E-/- animals, either splenectomized or spleen-intact. Homing into the BM of P/E-/- recipient mice was further compromised when a function-blocking VCAM-1 antibody was administered. Circulating HPC, 14 hr after transplantation, were greatly increased in P/E-/- mice treated with anti-VCAM-1 compared with P/E-/- mice treated with just IgG or wild-type mice treated with either anti-VCAM-1 or IgG. Our results indicate that endothelial selectins play an important role in HPC homing to the BM. Optimal recruitment of HPC after lethal doses of irradiation requires the combined action of both selectins and VCAM-1 expressed on endothelium of the BM.

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Figures

Figure 1

Figure 1

Survival of wild-type and P/E−/− mice after BMT. Recipient mice were lethally irradiated and transplanted with 5 × 104 wild-type BM cells. Animals were transferred to a microisolator unit, fed sterile food and water, and observed daily. n = 15–28; P < 0.0001.

Figure 2

Figure 2

Neutrophil recovery after BMT. Lethally irradiated (A) wild-type and (B) P/E−/− mice were transplanted with 5 × 104, 5 × 105, or 5 × 106 wild-type BM cells. Total leukocyte counts were obtained on days 10, 15, and 20, and absolute neutrophil numbers were determined from Wright-stained smears. ∗, None of the transplanted mice of this group reached day 20; n = 4–8.

Figure 3

Figure 3

Transient neutropenia induced by sublethal irradiation. Wild-type and P/E−/− mice were irradiated with 7.5 Gy and allowed to recover in a microisolator unit. Mice were divided into two groups by littermate pairs and leukocyte counts were monitored. ∗ indicates the time of death of a wild-type mouse, and # indicates the time of death of a P/E−/− mouse. n = 11–12.

Figure 4

Figure 4

Homing of hematopoietic progenitors. Freshly isolated wild-type BM cells (5 × 106 to 1 × 107) were injected into lethally irradiated wild-type (striated column) and P/E−/− (solid column) recipients. Progenitor homing was assayed as described in Materials and Methods. The percent of homed CFU-C activity, in two pooled experiments, is expressed per organ for (A) nonsplenectomized, n = 7 and (B) splenectomized mice, n = 9–12. ∗, P < 0.03; #, P = 0.006 compared with wild-type animals.

Figure 5

Figure 5

Homing to BM of hematopoietic progenitors in splenectomized wild-type and P/E−/− mice. Lethally irradiated recipient mice were injected with wild-type BM cells with control rat IgG1 or anti-VCAM-1 antibodies. CFU-Cs were determined from the recipient BM 14 hr after injection. n = 8–11. ∗, P < 0.001 compared with wild-type animals treated with IgG or anti-VCAM-1.

Figure 6

Figure 6

Hematopoietic colonies after 13 days in culture. (A) Aliquot of wild-type BM cells before injection (input cells). (B and C) The low-density cell fraction was isolated from 0.5 ml of blood of lethally irradiated recipients 14 hr after injection of wild-type BM cells. After 13 days of culture, very few colonies grew from the blood of wild-type recipient mice treated with IgG (B) or VCAM-1 antibody (not shown; see Table 2). However, many large colonies (>3 mm) grew from the blood of (C) P/E−/− recipients treated with anti-VCAM-1 (arrow).

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