9164933

pubmed:Citation

11

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.

http://linkedlifedata.com/resource/pubmed/journal/2985117R

http://linkedlifedata.com/resource/pubmed/chemical/Antigens, CD34, http://linkedlifedata.com/resource/pubmed/chemical/FLT3 protein, human, http://linkedlifedata.com/resource/pubmed/chemical/Flt3 protein, mouse, http://linkedlifedata.com/resource/pubmed/chemical/Proto-Oncogene Proteins, http://linkedlifedata.com/resource/pubmed/chemical/Proto-Oncogene Proteins c-kit, http://linkedlifedata.com/resource/pubmed/chemical/Receptor Protein-Tyrosine Kinases, http://linkedlifedata.com/resource/pubmed/chemical/Recombinant Proteins, http://linkedlifedata.com/resource/pubmed/chemical/Thrombopoietin, http://linkedlifedata.com/resource/pubmed/chemical/Transforming Growth Factor beta, http://linkedlifedata.com/resource/pubmed/chemical/Tumor Necrosis Factor-alpha, http://linkedlifedata.com/resource/pubmed/chemical/fms-Like Tyrosine Kinase 3

Jun

pubmed-author:BorgeO JOJ, pubmed-author:HuD RDR, pubmed-author:JacobsenS ESE, pubmed-author:RamsfjellVV

1

NLM

5169-77

pubmed-meshheading:9164933-Animals, pubmed-meshheading:9164933-Antigens, CD34, pubmed-meshheading:9164933-Bone Marrow, pubmed-meshheading:9164933-Bone Marrow Cells, pubmed-meshheading:9164933-Cell Differentiation, pubmed-meshheading:9164933-Cell Lineage, pubmed-meshheading:9164933-Cells, Cultured, pubmed-meshheading:9164933-Hematopoietic Stem Cells, pubmed-meshheading:9164933-Humans, pubmed-meshheading:9164933-Mice, pubmed-meshheading:9164933-Proto-Oncogene Proteins, pubmed-meshheading:9164933-Proto-Oncogene Proteins c-kit, pubmed-meshheading:9164933-Receptor Protein-Tyrosine Kinases, pubmed-meshheading:9164933-Recombinant Proteins, pubmed-meshheading:9164933-Thrombopoietin, pubmed-meshheading:9164933-Transforming Growth Factor beta, pubmed-meshheading:9164933-Tumor Necrosis Factor-alpha, pubmed-meshheading:9164933-fms-Like Tyrosine Kinase 3

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.

Journal Article