Lack of alpha4 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 alpha4 integrin leads to embryonic lethality, to study its effects on adult hematopoiesis, we used animals with conditional excision of alpha4 integrin (alpha4Delta/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 alpha4 integrins display a competitive disadvantage in hematopoietic reconstitution compared to normal competitors. Although initial dominance of alpha4+ competitors is due to their better homing and proliferative expansion early after transplantation, a progressive decline in contribution of alpha4Delta/Delta hematopoiesis is compatible with neither normal homing nor normal function of alpha4Delta/Delta hematopoietic stem cells (HSCs) in post-homing hematopoiesis. In the absence of alpha4+ competitor cells, alpha4Delta/Delta 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 alpha4Delta/Delta cells are seen in tertiary transplants. Collectively, our data provide compelling evidence that under regenerative stress alpha4 integrin assumes a greater importance than for maintenance of steady-state hematopoiesis.