Gregory V. Priestley

Deletion of α4 Integrins from Adult Hematopoietic Cells Reveals Roles in Homeostasis, Regeneration, and Homing

ABSTRACT We have explored the functional implications of inducible α4 integrin deletion during adult hematopoiesis by generating a conditional-knockout mouse model, and we show that α4 integrin-deficient hematopoietic progenitor cells accumulate in the peripheral blood soon after interferon-induced gene deletion. Although their numbers gradually stabilize at a lower level, progenitor cell influx into the circulation continues at above-normal levels for more than 50 weeks. Concomitantly, a progressive accumulation of progenitors occurs within the spleen. In addition, the regeneration of erythroid and myeloid progenitor cells is delayed during stress hematopoiesis induced by phenylhydrazine or by 5-fluorouracil, suggesting impairment in early progenitor expansion in the absence of α4 integrin. Moreover, in transplantation studies, homing of α4 −/− cells to the bone marrow, but not to the spleen, is selectively impaired, and short-term engraftment is critically delayed in the early weeks after transplantation. Thus, conditional deletion of α4 integrin in adult mice is accompanied by a novel hematopoietic phenotype during both homeostasis and recovery from stress, a phenotype that is distinct from the ones previously described in α4 integrin-null chimeras and β1 integrin-conditional knockouts.

Cells with hemopoietic potential residing in muscle are itinerant bone marrow–derived cells

OBJECTIVE The nature of cells residing in muscle giving rise to hemopoietic colonies in vitro or hemopoietic reconstitution in vivo has been unclear. The goal of the present study was to characterize these cells and uncover their potential site of origin. MATERIALS AND METHODS Cells prepared from muscle were characterized for surface antigens (CD45, CD34, c-kit, Sca-1, CD31, VCAM-1), for their in vitro clonogenic capacity and in vivo repopulation potential either as unpurified cells or sorted subsets (CD45(+), CD45(-)). The presence of bone marrow (BM)-derived cells in muscle of mice reconstituted with marked BM cells before and after cytokine-induced mobilization was also examined. RESULTS Our data show: 1) The yield of CD45(+) cells is higher in muscle of neonates and young animals. Their composite phenotype does not favor contamination by blood. 2) The capacity of fresh muscle cell explants to give rise to colonies in vitro and hemopoietic reconstitution in vivo is associated with CD45(+) cells. 3) Irradiated recipients reconstituted with marked BM cells harbor marked BM-derived cells (CD45(+) or CD45(-)) in their muscle several months after transplant. 4) Cytokine-induced mobilization of transplanted animals modestly increases the yield of BM-derived cells recovered from muscle, unlike the yields from spleen, liver, or peripheral blood (PB). CONCLUSIONS Our data suggest a reinterpretation of previously published conclusions: hemopoietic colonies derived from fresh muscle explants do not originate from transdifferentiated muscle cells, but from BM-derived cells residing in muscle; the hemopoietic reconstituting potential of muscle cells is likewise attributed to these cells.

Blockade of α6-Integrin Reveals Diversity in Homing Patterns Among Human, Baboon, and Murine Cells

Our understanding of the mechanisms by which intravenously transplanted hematopoietic stem/progenitor cells (HSPCs) home to and engraft the bone marrow (BM) remains incomplete, but participation of adhesion molecules has been documented. We here demonstrate that blockade of the alpha6-integrin enhanced BM homing of human and nonhuman primate BM-derived HSPCs by >60% in the xenogeneic transplant model and led to significantly improved engraftment. The effect was limited to BM-derived HSPCs, as granulocyte-colony-stimulating factor mobilized peripheral blood or cord blood HSPCs express little or no alpha6 integrin. By contrast, despite high alpha6 integrin expression, no effect of alpha6 blockade on murine BM-HSPCs homing/engraftment was observed.

A SURVEY OF ETHYLNITROSOUREA‐INDUCED RAT GLIOMAS FOR THE PRESENCE OF TUMOUR REJECTION ANTIGENS EXPRESSED IN VIVO

Spence A.M. & Priestley G. (1981) Neuropathology and Applied Neurobiology 7,63–75.

Cycling patterns of hemopoietic stem cell subpopulations in young and old BDF1 mice.

We have previously reported that two or more different subpopulations of bone marrow stem cells exist in mice as determined by cycling status of day-8 and day-14 CFU-S in long term bromodeoxyuridine (BrdU) infusion studies. In the present report, comparisons between cycling of stem cell subpopulations in old and young mice show that, while the general patterns persist, there are some statistically significant differences between corresponding time points of early and late CFU-S cycling patterns in young and old BDF1 mice. In both populations of CFU-S there exist cells which do not enter cycle over a five week period. The method which we have employed allowed the cycling measurements to be made in unstimulated steady-state bone marrow cell populations, since no cell death is caused in vivo.