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

Alpha4 integrin or VLA4 (CD49d/CD29) is a multitask molecule with wide expression within and outside the hematopoietic system. Because targeted ablation of alpha 4 integrin leads to embryonic lethality, to study its effects on adult hematopoiesis, we used animals with conditional excision of alpha 4 integrin (alpha 4(Delta/Delta)) 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 alpha 4 integrins display a competitive disadvantage in hematopoietic reconstitution compared to normal competitors. Although initial dominance of alpha 4(+) competitors is due to their better homing and proliferative expansion early after transplantation, a progressive decline in contribution of alpha 4(Delta/Delta) hematopoiesis is compatible with neither normal homing nor normal function of alpha 4(Delta/Delta) hematopoietic stem cells (HSCs) in post-homing hematopoiesis. in the absence of alpha 4(+) competitor cells, alpha 4(Delta/Delta) HSCs can establish long-term hematopoiesis in primary recipients, however, some resurgence of host hernatopoiesis is evident, and it becomes dominant in secondary transplants, so that no survivors with exclusively alpha 4(Delta/Delta) cells are seen in tertiary transplants. Collectively, our data provide compelling evidence that under regenerative stress alpha 4 integrin assumes a greater importance than for maintenance of steady-state hematopoiesis.