Lack of α4 integrin expression in stem cells restricts competitive function and self-renewal activity

Abstract

Alpha4 integrin or VLA4 (CD49d/CD29) is a multitask molecule with wide expression within and outside the hematopoietic system. Because targeted ablation of ␣4 integrin leads to embryonic lethality, to study its effects on adult hematopoiesis, we used animals with conditional excision of ␣4 integrin (␣4 ⌬/⌬ ) in hematopoietic cells. In such animals, we previously documented weakened bone marrow retention of progenitor cells during homeostasis and impaired homing and short-term engraftment after transplantation. In the present study we show that long-term repopulating cells lacking ␣4 integrins display a competitive disadvantage in hematopoietic reconstitution compared to normal competitors. Although initial dominance of ␣4 ؉ competitors is due to their better homing and proliferative expansion early after transplantation, a progressive decline in contribution of ␣4 ⌬/⌬ hematopoiesis is compatible with neither normal homing nor normal function of ␣4 ⌬/⌬ hematopoietic stem cells (HSCs) in post-homing hematopoiesis. In the absence of ␣4 ؉ competitor cells, ␣4 ⌬/⌬ HSCs can establish long-term hematopoiesis in primary recipients, however, some resurgence of host hematopoiesis is evident, and it becomes dominant in secondary transplants, so that no survivors with exclusively ␣4 ⌬/⌬ cells are seen in tertiary transplants. Collectively, our data provide compelling evidence that under regenerative stress ␣4 integrin assumes a greater importance than for maintenance of steady-state hematopoiesis. (Blood. 2006; 107:2959-2967)

α4 integrin levels on mobilized peripheral blood stem cells predict rapidity of engraftment in patients receiving autologous stem cell transplantation

“…Thus, determination of ␣4 integrin levels on HSCs compared with T cells should be the preferred analysis method, as shown in Figure 1D. In line with previous data about the importance of VLA4 for stem cell homing and engraftment derived from conditional deleted knockout mice systems 5,6 or antibody blocking experiments, 8 we show that the level of ␣4 integrin expression, but not ␣6 expression, on CD34 ϩ cells correlated significantly with PBSC engraftment, independent of the total number of CD34 ϩ cells and/or history of radiation therapy. Our finding may have clinical impact because anticipation of PBSC engraftment capacity from ␣4 Figure 1.…”

“…␣4␤1/VLA4 (CD49d/CD29), counter-receptor for VCAM-1 and fibronectin, as well as ␣6␤1/ VLA6/laminin receptor (CD49f/CD29) are ubiquitously expressed in human and mouse hematopoietic stem and progenitor cells, and both play a role in homing and engraftment of hematopoietic stem cells (HSCs). [2][3][4][5][6] Recent evidence from murine transplantation models suggests that ␣4-chain deletion 5 or treatment with functionblocking antibodies to ␣4 or ␣6 integrin 4 may impair hematopoietic engraftment. In contrast, it is reported that blockage with ␣6 integrin antibodies improves engraftment efficiency in human HSCs.…”

Mechanisms of G-CSF-mediated hematopoietic stem and progenitor mobilization

“…Conditional deletion of VLA-4 shows that this integrin is required for normal HSPC activity. 35 Similarly, genetic ablation of VCAM-1 leads to constitutive mobilization, that is enhanced with G-CSF. 36 Moreover, antibodies to VCAM-1 or VLA-4 mobilize HSPCs in both mice 37 and humans.…”

The pleiotropic effects of the SDF-1–CXCR4 axis in organogenesis, regeneration and tumorigenesis

“…28 Whether this integrin axis may compensate for the lack of CXCR4 signaling during colonization of fetal liver by HSC from CXCR4 À/À or SDF-1 À/À mice and guides engraftment of CXCR4 À/À fetal liver HSC cells after transplantation into normal littermates is not clear at this point. Alternatively, it is possible that engraftment of CXCR4 À/À HSC could be somehow compensated by the RDC1 receptor mentioned above, 16 or perhaps by a recently described homing mechanisms involving a calcium-sensing receptor.…”