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| Thrombopoietin directly and potently stimulates multilineage growth and progenitor cell expansion from primitive (CD34(+)CD38(-)) human bone marrow progenitor cells - Distinct and key interactions with the ligands for c-kit and flt3, and inhibitory EfFects of TGF-beta and TNF-alpha |
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| Author(s): Ramsfjell V, Borge OJ, Cui L, Jacobsen SEW |
| Source: JOURNAL OF IMMUNOLOGY Volume: 158 Issue: 11 Pages: 5169-5177 Published: JUN 1 1997 |
| Times Cited: 99 References: 50 |
| Abstract: Thrombopoietin (Tpo) is a primary regulator of megakaryocyte and platelet production. However, studies in c-mpl-deficient mice suggest that Tpo might also play an important role in early hemopoiesis. Here, the direct ability of Tpo to stimulate stroma-independent growth, multilineage differentiation, and progenitor cell expansion from single primitive CD34(+)CD38(-) human bone marrow cells was investigated. Tpo alone stimulated limited clonal growth, but synergized with c-kit ligand (KL), flt3 ligand (FL), or IL-3 to potently enhance clonogenic growth. Whereas KL and FL in combination stimulated the clonal growth of only 3% of CD34(+)CD38(-) cells, 40% of CD34(+)CD38(-) cells were recruited by KL+FL+Tpo, demonstrating that Tpo promotes the growth of a high fraction of CD34(+)CD38(-) progenitor cells, Additional cytokines (IL-3, IL-6, and erythropoietin (Epo)) did not significantly enhance clonal growth above that observed in response to KL(+)FL(+)Tpo. In contrast, Tpo enhanced clonogenic growth in response to KL+FL+IL-3+IL-6+Epo by as much as 80%, implicating a key role for this cytokine in early hemopoiesis, Importantly, we also demonstrate that the majority of Tpo-recruited CD34(+)CD38(-) progenitor cells have a multilineage differentiation potential, and that Tpo promotes prolonged expansion of multipotent progenitors. Specifically, whereas progenitor cells were reduced in cultures containing only KL+FL, addition of Tpo resulted in 40-fold expansion of multipotent progenitors following a 14-day incubation. Finally, we identified inhibitors of Tpo-induced progenitor cell growth, in that TGF-beta as well as TNF-alpha almost completely abrogated the growth of CD34(+)CD38(-) progenitor cells in response to Tpo alone as well as KL+FL+Tpo. |
| Document Type: Article |
| Language: English |
| Reprint Address: Ramsfjell, V (reprint author), UNIV LUND HOSP, DEPT INTERNAL MED, STEM CELL LAB, S-22185 LUND, SWEDEN |
Addresses:
1. HIPPLE CANC RES CTR, DAYTON, OH 45439 USA |
| Publisher: AMER ASSOC IMMUNOLOGISTS, 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 |
| Subject Category: Immunology |
| IDS Number: XA063 |
| ISSN: 0022-1767 |
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