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Proceedings of the National Academy of Sciences of the United States of America logoLink to Proceedings of the National Academy of Sciences of the United States of America
. 1992 May 1;89(9):4109–4113. doi: 10.1073/pnas.89.9.4109

Growth characteristics and expansion of human umbilical cord blood and estimation of its potential for transplantation in adults.

H E Broxmeyer 1, G Hangoc 1, S Cooper 1, R C Ribeiro 1, V Graves 1, M Yoder 1, J Wagner 1, S Vadhan-Raj 1, L Benninger 1, P Rubinstein 1, et al.
PMCID: PMC525642  PMID: 1373894

Abstract

We estimated whether single collections of cord blood contained sufficient cells for hematopoietic engraftment of adults by evaluating numbers of cord blood and adult bone marrow myeloid progenitor cells (MPCs) as detected in vitro with steel factor (SLF) and hematopoietic colony-stimulating factors (CSFs). SLF plus granulocyte-macrophage (GM)-CSF detected 8- to 11-fold more cord blood GM progenitors [colony-forming units (CFU)-GM] than cells stimulated with GM-CSF or 5637 conditioned medium (CM), growth factors previously used to estimate cord blood CFU-GM numbers. SLF plus erythropoietin (Epo) plus interleukin 3 (IL-3) enhanced detection of cord blood multipotential (CFU-GEMM) progenitors 15-fold compared to stimulation with Epo plus IL-3. Under the same conditions, bone marrow CFU-GM and CFU-GEMM were only enhanced in detection 2- to 4- and 6- to 8-fold. Increased detection of cord blood CFU-GEMM correlated directly with decreased detection of cord blood erythroid burst-forming units (BFU-E). In contrast, adult bone marrow CFU-GEMM and BFU-E numbers were both enhanced by SLF plus Epo plus IL-3. This suggests that most cord blood BFU-E may actually be CFU-GEMM. Cord blood collections (n = 17) contained numbers of MPCs (especially CFU-GM) similar to the number found in nine autologous bone marrow collections. To assess additional sources of MPCs, the peripheral blood of 1-day-old infants was assessed. However, average concentrations of MPCs circulating in these infants were only 30-46% that in their cord blood. Expansion of cord blood MPCs was also evaluated. Incubation of cord blood cells for 7 days with SLF resulted in 7.9-, 2.2-, and 2.7-fold increases in numbers of CFU-GM, BFU-E, and CFU-GEMM compared to starting numbers; addition of a CSF with SLF resulted in even greater expansion of MPCs. The results suggest that cord blood contains a larger number of early profile MPCs than previously recognized and that there are probably sufficient numbers of cells in a single cord blood collection to engraft an adult. Although the expansion data must be considered with caution, as human marrow repopulating cells cannot be assessed directly, in vitro expansion of cord blood stem and progenitor cells may be feasible for clinical transplantation.

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Selected References

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  1. Anderson D. M., Lyman S. D., Baird A., Wignall J. M., Eisenman J., Rauch C., March C. J., Boswell H. S., Gimpel S. D., Cosman D. Molecular cloning of mast cell growth factor, a hematopoietin that is active in both membrane bound and soluble forms. Cell. 1990 Oct 5;63(1):235–243. doi: 10.1016/0092-8674(90)90304-w. [DOI] [PubMed] [Google Scholar]
  2. Anderson D. M., Williams D. E., Tushinski R., Gimpel S., Eisenman J., Cannizzaro L. A., Aronson M., Croce C. M., Huebner K., Cosman D. Alternate splicing of mRNAs encoding human mast cell growth factor and localization of the gene to chromosome 12q22-q24. Cell Growth Differ. 1991 Aug;2(8):373–378. [PubMed] [Google Scholar]
  3. Auerbach A. D., Liu Q., Ghosh R., Pollack M. S., Douglas G. W., Broxmeyer H. E. Prenatal identification of potential donors for umbilical cord blood transplantation for Fanconi anemia. Transfusion. 1990 Oct;30(8):682–687. doi: 10.1046/j.1537-2995.1990.30891020324.x. [DOI] [PubMed] [Google Scholar]
  4. Bernstein I. D., Andrews R. G., Zsebo K. M. Recombinant human stem cell factor enhances the formation of colonies by CD34+ and CD34+lin- cells, and the generation of colony-forming cell progeny from CD34+lin- cells cultured with interleukin-3, granulocyte colony-stimulating factor, or granulocyte-macrophage colony-stimulating factor. Blood. 1991 Jun 1;77(11):2316–2321. [PubMed] [Google Scholar]
  5. Broxmeyer H. E., Bognacki J., Ralph P., Dörner M. H., Lu L., Castro-Malaspina H. Monocyte-macrophage-derived acidic isoferritins: normal feedback regulators of granulocyte-macrophage progenitor cells in vitro. Blood. 1982 Sep;60(3):595–607. [PubMed] [Google Scholar]
  6. Broxmeyer H. E., Cooper S., Lu L., Hangoc G., Anderson D., Cosman D., Lyman S. D., Williams D. E. Effect of murine mast cell growth factor (c-kit proto-oncogene ligand) on colony formation by human marrow hematopoietic progenitor cells. Blood. 1991 May 15;77(10):2142–2149. [PubMed] [Google Scholar]
  7. Broxmeyer H. E., Cooper S., Yoder M., Hangoc G. Human umbilical cord blood as a source of transplantable hematopoietic stem and progenitor cells. Curr Top Microbiol Immunol. 1992;177:195–204. doi: 10.1007/978-3-642-76912-2_15. [DOI] [PubMed] [Google Scholar]
  8. Broxmeyer H. E., Douglas G. W., Hangoc G., Cooper S., Bard J., English D., Arny M., Thomas L., Boyse E. A. Human umbilical cord blood as a potential source of transplantable hematopoietic stem/progenitor cells. Proc Natl Acad Sci U S A. 1989 May;86(10):3828–3832. doi: 10.1073/pnas.86.10.3828. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Broxmeyer H. E., Kurtzberg J., Gluckman E., Auerbach A. D., Douglas G., Cooper S., Falkenburg J. H., Bard J., Boyse E. A. Umbilical cord blood hematopoietic stem and repopulating cells in human clinical transplantation. Blood Cells. 1991;17(2):313–329. [PubMed] [Google Scholar]
  10. Broxmeyer H. E., Maze R., Miyazawa K., Carow C., Hendrie P. C., Cooper S., Hangoc G., Vadhan-Raj S., Lu L. The kit receptor and its ligand, steel factor, as regulators of hemopoiesis. Cancer Cells. 1991 Dec;3(12):480–487. [PubMed] [Google Scholar]
  11. Broxmeyer H. E. Self-renewal and migration of stem cells during embryonic and fetal hematopoiesis: important, but poorly understood events. Blood Cells. 1991;17(2):282–286. [PubMed] [Google Scholar]
  12. Broxmeyer H. E., Williams D. E. The production of myeloid blood cells and their regulation during health and disease. Crit Rev Oncol Hematol. 1988;8(3):173–226. doi: 10.1016/s1040-8428(88)80016-7. [DOI] [PubMed] [Google Scholar]
  13. Carow C. E., Hangoc G., Cooper S. H., Williams D. E., Broxmeyer H. E. Mast cell growth factor (c-kit ligand) supports the growth of human multipotential progenitor cells with a high replating potential. Blood. 1991 Nov 1;78(9):2216–2221. [PubMed] [Google Scholar]
  14. Douay L., Gorin N. C., Mary J. Y., Lemarie E., Lopez M., Najman A., Stachowiak J., Giarratana M. C., Baillou C., Salmon C. Recovery of CFU-GM from cryopreserved marrow and in vivo evaluation after autologous bone marrow transplantation are predictive of engraftment. Exp Hematol. 1986 Jun;14(5):358–365. [PubMed] [Google Scholar]
  15. English D., Lamberson R., Graves V., Akard L. P., McCarthy L. J., Jansen J. Semiautomated processing of bone marrow grafts for transplantation. Transfusion. 1989 Jan;29(1):12–16. doi: 10.1046/j.1537-2995.1989.29189101156.x. [DOI] [PubMed] [Google Scholar]
  16. Faille A., Maraninchi D., Gluckman E., Devergie A., Balitrand N., Ketels F., Dresch C. Granulocyte progenitor compartments after allogeneic bone marrow grafts. Scand J Haematol. 1981 Mar;26(3):202–214. doi: 10.1111/j.1600-0609.1981.tb01648.x. [DOI] [PubMed] [Google Scholar]
  17. Geissler K., Geissler W., Hinterberger W., Lechner K., Wurnig P. Circulating committed and pluripotent haemopoietic progenitor cells, in infants. Acta Haematol. 1986;75(1):18–22. doi: 10.1159/000206073. [DOI] [PubMed] [Google Scholar]
  18. Gluckman E., Broxmeyer H. A., Auerbach A. D., Friedman H. S., Douglas G. W., Devergie A., Esperou H., Thierry D., Socie G., Lehn P. Hematopoietic reconstitution in a patient with Fanconi's anemia by means of umbilical-cord blood from an HLA-identical sibling. N Engl J Med. 1989 Oct 26;321(17):1174–1178. doi: 10.1056/NEJM198910263211707. [DOI] [PubMed] [Google Scholar]
  19. Huang E., Nocka K., Beier D. R., Chu T. Y., Buck J., Lahm H. W., Wellner D., Leder P., Besmer P. The hematopoietic growth factor KL is encoded by the Sl locus and is the ligand of the c-kit receptor, the gene product of the W locus. Cell. 1990 Oct 5;63(1):225–233. doi: 10.1016/0092-8674(90)90303-v. [DOI] [PubMed] [Google Scholar]
  20. Jacobsen N., Broxmeyer H. E., Grossbard E., Moore M. A. Colony-forming units in diffusion chambers (CFU-d) and colony-forming units in agar culture (CFU-c) obtained from normal human bone marrow: a possible parent-progeny relationship. Cell Tissue Kinet. 1979 Mar;12(2):213–226. doi: 10.1111/j.1365-2184.1979.tb00127.x. [DOI] [PubMed] [Google Scholar]
  21. Jones R. J., Sharkis S. J., Celano P., Colvin O. M., Rowley S. D., Sensenbrenner L. L. Progenitor cell assays predict hematopoietic reconstitution after syngeneic transplantation in mice. Blood. 1987 Oct;70(4):1186–1192. [PubMed] [Google Scholar]
  22. Ma D. D., Varga D. E., Biggs J. C. Donor marrow progenitors (CFU-Mix, BFU-E and CFU-GM) and haemopoietic engraftment following HLA matched sibling bone marrow transplantation. Leuk Res. 1987;11(2):141–147. doi: 10.1016/0145-2126(87)90019-1. [DOI] [PubMed] [Google Scholar]
  23. McGlave P. B. An expanded role for cord blood transplantation. Blood Cells. 1991;17(2):330–337. [PubMed] [Google Scholar]
  24. Migliaccio G., Migliaccio A. R., Valinsky J., Langley K., Zsebo K., Visser J. W., Adamson J. W. Stem cell factor induces proliferation and differentiation of highly enriched murine hematopoietic cells. Proc Natl Acad Sci U S A. 1991 Aug 15;88(16):7420–7424. doi: 10.1073/pnas.88.16.7420. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Moore M. A. Review: Stratton Lecture 1990. Clinical implications of positive and negative hematopoietic stem cell regulators. Blood. 1991 Jul 1;78(1):1–19. [PubMed] [Google Scholar]
  26. Nichols C. R., Tricot G., Williams S. D., van Besien K., Loehrer P. J., Roth B. J., Akard L., Hoffman R., Goulet R., Wolff S. N. Dose-intensive chemotherapy in refractory germ cell cancer--a phase I/II trial of high-dose carboplatin and etoposide with autologous bone marrow transplantation. J Clin Oncol. 1989 Jul;7(7):932–939. doi: 10.1200/JCO.1989.7.7.932. [DOI] [PubMed] [Google Scholar]
  27. Rowley S. D., Zuehlsdorf M., Braine H. G., Colvin O. M., Davis J., Jones R. J., Saral R., Sensenbrenner L. L., Yeager A., Santos G. W. CFU-GM content of bone marrow graft correlates with time to hematologic reconstitution following autologous bone marrow transplantation with 4-hydroperoxycyclophosphamide-purged bone marrow. Blood. 1987 Jul;70(1):271–275. [PubMed] [Google Scholar]
  28. Spitzer G., Verma D. S., Fisher R., Zander A., Vellekoop L., Litam J., McCredie K. B., Dicke K. A. The myeloid progenitor cell--its value in predicting hematopoietic recovery after autologous bone marrow transplantation. Blood. 1980 Feb;55(2):317–323. [PubMed] [Google Scholar]
  29. Sutherland H. J., Lansdorp P. M., Henkelman D. H., Eaves A. C., Eaves C. J. Functional characterization of individual human hematopoietic stem cells cultured at limiting dilution on supportive marrow stromal layers. Proc Natl Acad Sci U S A. 1990 May;87(9):3584–3588. doi: 10.1073/pnas.87.9.3584. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Tavassoli M. Embryonic and fetal hemopoiesis: an overview. Blood Cells. 1991;17(2):269–286. [PubMed] [Google Scholar]
  31. Williams D. E., Eisenman J., Baird A., Rauch C., Van Ness K., March C. J., Park L. S., Martin U., Mochizuki D. Y., Boswell H. S. Identification of a ligand for the c-kit proto-oncogene. Cell. 1990 Oct 5;63(1):167–174. doi: 10.1016/0092-8674(90)90297-r. [DOI] [PubMed] [Google Scholar]
  32. Xiao M., Leemhuis T., Broxmeyer H. E., Lu L. Influence of combinations of cytokines on proliferation of isolated single cell-sorted human bone marrow hematopoietic progenitor cells in the absence and presence of serum. Exp Hematol. 1992 Feb;20(2):276–279. [PubMed] [Google Scholar]
  33. Zsebo K. M., Wypych J., McNiece I. K., Lu H. S., Smith K. A., Karkare S. B., Sachdev R. K., Yuschenkoff V. N., Birkett N. C., Williams L. R. Identification, purification, and biological characterization of hematopoietic stem cell factor from buffalo rat liver--conditioned medium. Cell. 1990 Oct 5;63(1):195–201. doi: 10.1016/0092-8674(90)90300-4. [DOI] [PubMed] [Google Scholar]
  34. de Vries P., Brasel K. A., Eisenman J. R., Alpert A. R., Williams D. E. The effect of recombinant mast cell growth factor on purified murine hematopoietic stem cells. J Exp Med. 1991 May 1;173(5):1205–1211. doi: 10.1084/jem.173.5.1205. [DOI] [PMC free article] [PubMed] [Google Scholar]

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