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The Effects of Transforming Growth Factor ß₃ on the Growth of Highly Enriched Hematopoietic Progenitor Cells Derived from Normal Human Bone Marrow and Peripheral Blood¹

Memorial Sloan-Kettering Cancer Center, Laboratory of Hematopoietic Cell Kinetics, New York, New York 10021 [A. S., C. L., A. P., S. G., B. D. C.]; New York Medical College, Cancer Research Institute, Valhalla, New York 10595 [Z. D., J. S.]; and Oncogene Science, Inc., Department of Cancer Therapeutics, Manhasset, New York 11030 [J. D. H., P. t-D., K. K. I.]

The effects of transforming growth factor ß₃ (TGF-ß₃) on growth in semisolid cultures of enriched hematopoietic progenitors derived from normal human marrow and blood were evaluated. Conditioned media from the Mo-T cell line (MoCM) were the source of colony-stimulating factors used to optimally stimulate primitive progenitors. To assess whether a proportion of granulocyte/monocyte (GM) progenitors were prevented from cycling, all sizes of GM aggregates were evaluated from 3 to 20 days. The activity of TGF-ß₃ on the growth of erythroid burst-forming units (BFU-E) and granulocyte-macrophage colony-forming units (CFU-GM) was similar to that observed for TGF-ß₁.

TGF-ß₃ (10, 100, and 1000 pmol/liter), added initially or 72 h after initiation of culture, did not significantly affect the total number of marrow GM aggregates at 3, 7, 14, and 20 days, but TGF-ß₃ (1000 pmol/liter), added initially, reduced the total number of blood GM aggregates. This suggests that some blood GM progenitors might be blocked from cycling but that the great majority of marrow GM progenitors are not blocked. Whether TGF-ß₃ (10, 100, and 1000 pmol/liter) was added initially or after 72h of stimulation by MoCM, there was a dose-dependent reduction of marrow and blood GM colony size even when the total number of colonies was unaffected.

TGF-ß₃ (10, 100, and 1000 pmol/liter), added initially or at 72 h, reduced in a dose-dependent manner the size of marrow and blood-derived BFU-E. TGF-ß₃ (1000 pmol/liter) was more likely to reduce the total number of marrow and blood BFU-E, and this increased sensitivity of the erythroid lineage may prevent the development of this population in colonies derived from multipotential colony-forming unit-granulocyte/erythroid/monocyte (CFU-GEM).

The results suggest that the main effect of TGF-ß₃ and TGF-ß₁ is to slow the rate of proliferation of hematopoietic progenitors rather than to prevent them from beginning proliferation. This results in a reduction in colony size which prevents the identification of primitive versus mature progenitor on the basis of standard criteria of colony size.

¹ Research supported by National Cancer Institute Grant CA20194; the Enid A. Haupt Charitable Trust; the Samuel and May Rudin Foundation; and the United Leukemia Fund. Z. D. was supported by NCI Grants R37 CA23296 and RO128504. J. D. H. and K. K. I. were supported by a collaborative research agreement between Pfizer, Inc., and Oncogene Science, Inc.

² To whom requests for reprints should be addressed, at Memorial Sloan-Kettering Cancer Center, Laboratory of Hematopoietic Cell Kinetics, 1275 York Avenue, New York, NY 10021

Received 3/18/91. Accepted 7/ 3/91.

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