In vivo administration of recombinant methionyl human stem cell factor expands the number of human marrow hematopoietic stem cells

J. Tong, M. S. Gordon, Edward Srour, R. J. Cooper, A. Orazi, I. McNiece, R. Hoffman

Research output: Contribution to journalArticle

54 Citations (Scopus)

Abstract

A growing number of in vitro studies suggest that recombinant human stem cell factor (SCF) is capable of augmenting the proliferative capacity of human hematopoietic progenitor cells (HPC) and stem cells (HSC). We further evaluated this biologic effect by analyzing the response of bone marrow (BM) HPCs and HSCs to the administration of SCF in eight patients with locally advanced or metastatic breast cancer who were enrolled in an ongoing phase I study. SCF was administered for 14 days by daily subcutaneous injection at dosages of 10, 25, or 50 μg/kg/ d. BM CD34+ HLA-DR+ and CD34+ HLA-DR- CD15- cells, previously shown by our laboratory to be enriched for various classes of differentiated and primitive HPCs, respectively, were quantitated in BM samples on day 0 (pretreatment) and day 15 (posttreatment). These CD34+ HLA-DR+ and CD34+ HLA-DR- CD15- cells were then isolated by cell-sorting and assayed for several classes of HPCs, including the high-proliferative potential colony-forming cell (HPP-CFC), the burst-forming unit-megakaryocyte (BFU-MK), and the long-term BM culture-initiating cell (LTBMC-IC). SCF administration resulted in a 3.3-fold (range, 1.4- to 18.8-fold; P = .018) increase in the absolute numbers of CD34+ cells, a 3.7-fold (range, 1.2- to 8.2-fold; P = .028) increase in the absolute numbers of CD34+ HLA-DR+ cells, and a 2.4-fold (range, 1.1- to 29.3-fold; P = .010) increase in the absolute numbers of CD34+ HLA-DR- CD15- cells. Following the infusion of SCF, a statistically significant increase in the absolute numbers of HPP-CFC (P = .018), BFU-MK (P = .046), CFU-granulocyte, erythrocyte, monocyte, megakaryocyte (CFU-GEMM; P = .043), BFU-erythrocyte (BFU-E; P = .043), CFU-granulocyte, macrophage (CFU-GM; P = .045), and CFU-megakaryocyte (CFU-MK; P = .028) per milliliter of marrow was observed. Stromal cell-free LTBMCs supplemented with SCF and interleukin-3 (IL-3), initiated with CD34+ HLA-DR- CD15- cells obtained on day 0, produced viable cells for 9.6 weeks, compared with 11.5 weeks for LTBMCs initiated with CD34+ HLA-DR- CD15- cells obtained on day 15. Cumulative cellular production by LTBMCs initiated with day 15 CD34+ HLA-DR- CD15- cells was statistically greater than that by day 0 LTBMCs (P = .031). These same cultures produced CFU-GM for 6.3 weeks (day 0) versus 9 weeks (day 15). Cumulative production of CFU-GM during the period of LTBMC was statistically greater when day 15 CD34+ HLA-DR- CD15- cells served as the initiating cell population compared with the same subpopulation obtained on day 0 (2.1- to 18-fold increase; P = .010). We conclude that the in vivo administration of SCF to humans results in a statistically significant expansion in numbers and proliferative capacity of both differentiated and primitive HPCs. These studies suggest that in vivo SCF administration may be useful for improving the quality of BM grafts to be used for both autologous and allogeneic BM transplantation.

Original languageEnglish (US)
Pages (from-to)784-791
Number of pages8
JournalBlood
Volume82
Issue number3
StatePublished - Aug 1 1993

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HLA-DR Antigens
Hematopoietic Stem Cells
Stem cells
Stem Cell Factor
Bone Marrow
Bone
Megakaryocytes
Granulocyte-Macrophage Progenitor Cells
Granulocytes
ancestim
Erythrocytes
Macrophages
Interleukin-3
Myeloid Progenitor Cells
Sorting
Cell culture
Grafts
Erythroid Precursor Cells
Homologous Transplantation
Subcutaneous Injections

ASJC Scopus subject areas

  • Hematology

Cite this

Tong, J., Gordon, M. S., Srour, E., Cooper, R. J., Orazi, A., McNiece, I., & Hoffman, R. (1993). In vivo administration of recombinant methionyl human stem cell factor expands the number of human marrow hematopoietic stem cells. Blood, 82(3), 784-791.

In vivo administration of recombinant methionyl human stem cell factor expands the number of human marrow hematopoietic stem cells. / Tong, J.; Gordon, M. S.; Srour, Edward; Cooper, R. J.; Orazi, A.; McNiece, I.; Hoffman, R.

In: Blood, Vol. 82, No. 3, 01.08.1993, p. 784-791.

Research output: Contribution to journalArticle

Tong, J, Gordon, MS, Srour, E, Cooper, RJ, Orazi, A, McNiece, I & Hoffman, R 1993, 'In vivo administration of recombinant methionyl human stem cell factor expands the number of human marrow hematopoietic stem cells', Blood, vol. 82, no. 3, pp. 784-791.
Tong, J. ; Gordon, M. S. ; Srour, Edward ; Cooper, R. J. ; Orazi, A. ; McNiece, I. ; Hoffman, R. / In vivo administration of recombinant methionyl human stem cell factor expands the number of human marrow hematopoietic stem cells. In: Blood. 1993 ; Vol. 82, No. 3. pp. 784-791.
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T1 - In vivo administration of recombinant methionyl human stem cell factor expands the number of human marrow hematopoietic stem cells

AU - Tong, J.

AU - Gordon, M. S.

AU - Srour, Edward

AU - Cooper, R. J.

AU - Orazi, A.

AU - McNiece, I.

AU - Hoffman, R.

PY - 1993/8/1

Y1 - 1993/8/1

N2 - A growing number of in vitro studies suggest that recombinant human stem cell factor (SCF) is capable of augmenting the proliferative capacity of human hematopoietic progenitor cells (HPC) and stem cells (HSC). We further evaluated this biologic effect by analyzing the response of bone marrow (BM) HPCs and HSCs to the administration of SCF in eight patients with locally advanced or metastatic breast cancer who were enrolled in an ongoing phase I study. SCF was administered for 14 days by daily subcutaneous injection at dosages of 10, 25, or 50 μg/kg/ d. BM CD34+ HLA-DR+ and CD34+ HLA-DR- CD15- cells, previously shown by our laboratory to be enriched for various classes of differentiated and primitive HPCs, respectively, were quantitated in BM samples on day 0 (pretreatment) and day 15 (posttreatment). These CD34+ HLA-DR+ and CD34+ HLA-DR- CD15- cells were then isolated by cell-sorting and assayed for several classes of HPCs, including the high-proliferative potential colony-forming cell (HPP-CFC), the burst-forming unit-megakaryocyte (BFU-MK), and the long-term BM culture-initiating cell (LTBMC-IC). SCF administration resulted in a 3.3-fold (range, 1.4- to 18.8-fold; P = .018) increase in the absolute numbers of CD34+ cells, a 3.7-fold (range, 1.2- to 8.2-fold; P = .028) increase in the absolute numbers of CD34+ HLA-DR+ cells, and a 2.4-fold (range, 1.1- to 29.3-fold; P = .010) increase in the absolute numbers of CD34+ HLA-DR- CD15- cells. Following the infusion of SCF, a statistically significant increase in the absolute numbers of HPP-CFC (P = .018), BFU-MK (P = .046), CFU-granulocyte, erythrocyte, monocyte, megakaryocyte (CFU-GEMM; P = .043), BFU-erythrocyte (BFU-E; P = .043), CFU-granulocyte, macrophage (CFU-GM; P = .045), and CFU-megakaryocyte (CFU-MK; P = .028) per milliliter of marrow was observed. Stromal cell-free LTBMCs supplemented with SCF and interleukin-3 (IL-3), initiated with CD34+ HLA-DR- CD15- cells obtained on day 0, produced viable cells for 9.6 weeks, compared with 11.5 weeks for LTBMCs initiated with CD34+ HLA-DR- CD15- cells obtained on day 15. Cumulative cellular production by LTBMCs initiated with day 15 CD34+ HLA-DR- CD15- cells was statistically greater than that by day 0 LTBMCs (P = .031). These same cultures produced CFU-GM for 6.3 weeks (day 0) versus 9 weeks (day 15). Cumulative production of CFU-GM during the period of LTBMC was statistically greater when day 15 CD34+ HLA-DR- CD15- cells served as the initiating cell population compared with the same subpopulation obtained on day 0 (2.1- to 18-fold increase; P = .010). We conclude that the in vivo administration of SCF to humans results in a statistically significant expansion in numbers and proliferative capacity of both differentiated and primitive HPCs. These studies suggest that in vivo SCF administration may be useful for improving the quality of BM grafts to be used for both autologous and allogeneic BM transplantation.

AB - A growing number of in vitro studies suggest that recombinant human stem cell factor (SCF) is capable of augmenting the proliferative capacity of human hematopoietic progenitor cells (HPC) and stem cells (HSC). We further evaluated this biologic effect by analyzing the response of bone marrow (BM) HPCs and HSCs to the administration of SCF in eight patients with locally advanced or metastatic breast cancer who were enrolled in an ongoing phase I study. SCF was administered for 14 days by daily subcutaneous injection at dosages of 10, 25, or 50 μg/kg/ d. BM CD34+ HLA-DR+ and CD34+ HLA-DR- CD15- cells, previously shown by our laboratory to be enriched for various classes of differentiated and primitive HPCs, respectively, were quantitated in BM samples on day 0 (pretreatment) and day 15 (posttreatment). These CD34+ HLA-DR+ and CD34+ HLA-DR- CD15- cells were then isolated by cell-sorting and assayed for several classes of HPCs, including the high-proliferative potential colony-forming cell (HPP-CFC), the burst-forming unit-megakaryocyte (BFU-MK), and the long-term BM culture-initiating cell (LTBMC-IC). SCF administration resulted in a 3.3-fold (range, 1.4- to 18.8-fold; P = .018) increase in the absolute numbers of CD34+ cells, a 3.7-fold (range, 1.2- to 8.2-fold; P = .028) increase in the absolute numbers of CD34+ HLA-DR+ cells, and a 2.4-fold (range, 1.1- to 29.3-fold; P = .010) increase in the absolute numbers of CD34+ HLA-DR- CD15- cells. Following the infusion of SCF, a statistically significant increase in the absolute numbers of HPP-CFC (P = .018), BFU-MK (P = .046), CFU-granulocyte, erythrocyte, monocyte, megakaryocyte (CFU-GEMM; P = .043), BFU-erythrocyte (BFU-E; P = .043), CFU-granulocyte, macrophage (CFU-GM; P = .045), and CFU-megakaryocyte (CFU-MK; P = .028) per milliliter of marrow was observed. Stromal cell-free LTBMCs supplemented with SCF and interleukin-3 (IL-3), initiated with CD34+ HLA-DR- CD15- cells obtained on day 0, produced viable cells for 9.6 weeks, compared with 11.5 weeks for LTBMCs initiated with CD34+ HLA-DR- CD15- cells obtained on day 15. Cumulative cellular production by LTBMCs initiated with day 15 CD34+ HLA-DR- CD15- cells was statistically greater than that by day 0 LTBMCs (P = .031). These same cultures produced CFU-GM for 6.3 weeks (day 0) versus 9 weeks (day 15). Cumulative production of CFU-GM during the period of LTBMC was statistically greater when day 15 CD34+ HLA-DR- CD15- cells served as the initiating cell population compared with the same subpopulation obtained on day 0 (2.1- to 18-fold increase; P = .010). We conclude that the in vivo administration of SCF to humans results in a statistically significant expansion in numbers and proliferative capacity of both differentiated and primitive HPCs. These studies suggest that in vivo SCF administration may be useful for improving the quality of BM grafts to be used for both autologous and allogeneic BM transplantation.

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