Inhibition of early murine hemopoietic progenitor cell proliferation after in vivo locoregional administration of transforming growth factor-beta 1.

Abstract

Transforming growth factor-beta 1 (TGF beta 1) has been shown in vitro to be a potent negative regulator of growth and differentiation of early hemopoietic progenitor cells, but not of more mature progenitors. However, little information is yet available regarding similar effects in vivo. We have developed an approach whereby TGF beta 1 can be administered locoregionally to the bone marrow via direct injection into the femoral artery. Our studies show that intrafemoral administration of a single bolus dose of TGF beta 1 potently inhibits the baseline and IL-3-driven proliferation of bone marrow cells. This inhibition is relatively selective for the earlier multipotential granulocyte, erythroid, megakaryocyte, and macrophage CFU progenitor cells since these are completely inhibited while the more differentiated CFU assayed in culture colonies are inhibited by about 50%. The inhibition of hemopoietic progenitor growth and differentiation is both time and dose dependent with the maximal effect on the marrow observed at 24 h with doses greater than or equal to 5 micrograms/mouse, and the effect is reversed at later times. A possible practical implication of these in vivo results could be the use of TGF beta 1 to protect stem cells in the bone marrow from the myelotoxic effects of chemotherapeutic drugs.

Mechanisms controlling hematopoietic stem cell functions during normal hematopoiesis and hematological malignancies

“…87,88 Early in vitro studies in both human and mouse suggested that TGF-β1 and 3 mediated antiproliferative effects on hematopoietic stem/progenitor populations. 89 However, a precise understanding of the role of TGF-β signaling in vivo has been difficult to obtain due to the complexity of the phenotypes exhibited by mice deficient in TGF-β signaling components. The majority of Tgf-β1 −/− mice die in utero at day E10.5 from multiple developmental defects, whereas the few that survive to adulthood develop a wasting disease due to an autoinflammatory condition.…”

“…Early in vitro studies in both human and mouse suggested that TGF‐ β 1 and 3 mediated antiproliferative effects on hematopoietic stem/progenitor populations 89. However, a precise understanding of the role of TGF‐ β signaling in vivo has been difficult to obtain due to the complexity of the phenotypes exhibited by mice deficient in TGF‐ β signaling components.…”