DOI
https://doi.org/10.25772/TRNZ-3A78
Defense Date
1992
Document Type
Dissertation
Degree Name
Doctor of Philosophy
Department
Pharmacology & Toxicology
First Advisor
Steven Grant
Abstract
The activity of protein kinase C (PK-C) has been implicated in regulating the growth and differentiation of both normal and neoplastic hematopoietic cells. We have examined the effects of the PK-C activators, phorbol 12,13- dibutyrate, mezerein, and bryostatin 1, on the proliferation and lineage commitment of enriched CD34+ human myeloid progenitor cells stimulated by lL-3, GM-CSF, stem cell factor and the lL-3/GM-CSF hybrid cytokine plXY321. Coadministration of these PK-C activators with plateau concentrations of rlL-3 or rGM-CSF induced 100-150% increase in the number of day 14 CFU-GM.with a selective stimulation on neutrophil and macrophage lineages while inhibiting eosinophilic growth. plXY321 stimulated an equivalent number of CFU-GM, including a predominant eosinophilic component, when compared to the combination of saturating levels of GM-CSF and lL-3. Bryostatin 1, when coadministered with plXY321 (or with the combination of lL-3 and GM-CSF), selectively enhanced the growth of neutrophilic and monocytic lineages while inhibiting eosinophil development. The inhibition of eosinophil colonies by bryostatin 1 was not mimicked by the coadministration of rSCF, rG-CSF or rCSF-1 with plXY321. Furthermore, neutralizing antibodies to rG-CSF and rCSF-1 failed to block potentiation of neutrophil or macrophage colony formation stimulated by bryostatin 1 in conjunction with plXY321, suggesting that accessory cell effects are not solely responsible for this phenomenona. rSCF synergistically enhanced plXY321 induced colony formation by an average of 144% by selectively stimulating neutrophilic and eosinophilic growth. Coadministration of bryostatin 1 with rSCF and plXY321 further increased colony formation by an average of 81%. This combination selectively stimulated cells of the macrophage lineage, and inhibited eosinophil differentiation. However, bryostatin 1 inhibited erythroid (BFU-E) and erythroid/myeloid mixed (CFU-GEMM) colonies induced by plXY321 alone or in combination with rSCF. Together these results indicate that 1) PK-C activity is involved in the growth and lineage commitment of early and committed myeloid progenitor cells. 2) Pharmacologic manipulation of PK-C may regulate the growth and differentiation of those cells exposed to early hematopoietic growth factors. This study raises the possibility that pharmacologic intervention at PK-C,in conjunction with hematopoietic growth factors, might be useful in the ex vivo expansion of hematopoietic progenitor cells.
Rights
© The Author
Is Part Of
VCU University Archives
Is Part Of
VCU Theses and Dissertations
Date of Submission
11-29-2017
Comments
Scanned, with permission from the author, from the original print version, which resides in University Archives.