194: A molecular profile of endothelial cell-derived growth factors that regulate stem cell self-renewal
Year: 2007
Type: article
Abstract: Several molecular pathways that regulate hematopoietic stem cell (HSC) self-renewal in the mouse have recently been elucidated, including Notch, HOXB4, Wnt and bone morphogenetic protein signaling pathways. However, full elucidation of the intrinsic and extrinsic mechanisms that regulate human HSC self renewal has yet to be realized. As a model for identifying extrinsic factors that stimulate human HSC self-renewal, we have studied the capacity for vascular endothelial cells to support human HSC expansion ex vivo. We have found that primary human brain-derived endothelial cells (HUBECs), unlike all other tissue sources of human ECs we have studied, support a 1-2 log amplification of human bone marrow and cord blood HSCs in short term culture, in the absence of contact (Blood 105:576-83, Blood 100:4433-39). These results indicate that HUBECs are an ideal resource to identify novel soluble growth factors that trigger human HSC self-renewal and expansion. In this study, we applied a comprehensive gene expression strategy to identify the secreted gene products differentially expressed by HUBECs as compared to ECs from a wide range of non-brain tissues, including aorta, pulmonary artery, iliac artery, dermal artery and coronary artery. RNA was isolated from 9 different non-brain ECs and 6 different HUBECs, each of which has been shown by our laboratory to promote human HSC expansion in vitro. Samples were hybridized to Operon Human v.3 oligonucleotide arrays. Applying both an unsupervised hierarchical clustering analysis and a supervised Bayesian ANOVA analysis, 300 genes from these analyses were classified as being either membrane bound or soluble gene products based on the database of membrane-associated/soluble gene products generated by Diehn et al. (PLoS Genetics epub 2006). Thirty-two of these were annotated to be secreted gene products. Several novel growth factors not typically associated with hematopoiesis were identified. We have found that one of these factors, adrenomedullin, a vasodilator not known to have hematopoietic function, induces the proliferation of human BM CD34+CD38-lin- HSCs in single cell cultures and promotes the quantitative expansion of human BM CD34+ progenitor cells in vitro. This molecular signature of HUBECs provides a unique resource for the discovery and characterization of novel soluble factors that regulate human HSC fate.
Authors: H. Himburg, G.G. Muramoto, A.B. Salter, J. Zhai, J.-T.A. Chi, J.P. Chute
Institution: Duke Medical Center
Language: English
Subfield: Hematology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $3,650
OpenAlex ID: W2083172275