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

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Abstract
Alpha4 integrin or VLA4 (CD49d/CD29) is a multitask molecule with wide expression within and outside the hematopoietic system. Because targeted ablation of α4 integrin leads to embryonic lethality, to study its effects on adult hematopoiesis, we used animals with conditional excision of α4 integrin (α4Δ/Δ) 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 α4 integrins display a competitive disadvantage in hematopoietic reconstitution compared to normal competitors. Although initial dominance of α4+ competitors is due to their better homing and proliferative expansion early after transplantation, a progressive decline in contribution of α4Δ/Δ hematopoiesis is compatible with neither normal homing nor normal function of α4Δ/Δ hematopoietic stem cells (HSCs) in post-homing hematopoiesis. In the absence of α4+ competitor cells, α4Δ/Δ 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 α4Δ/Δ cells are seen in tertiary transplants. Collectively, our data provide compelling evidence that under regenerative stress α4 integrin assumes a greater importance than for maintenance of steady-state hematopoiesis.