Abstract
IntroductionHematopoietic stem cells (HSCs) follow a genetically programmed pattern of migration during development. Extracellular matrix and adhesion molecules, as well as chemokines and their receptors, are important in adult HSC migration. However, little is known about the role these molecules play at earlier developmental stages.MethodsWe have analyzed by quantitative polymerase chain reaction (qPCR) array the expression pattern of extracellular matrix and adhesion molecules as well as chemokines and chemokine receptors in Lineage-Sca-1+c-Kit+ (LSK) cells at different stages of development, in order to characterize the role played by these molecules in LSK. Data were represented by volcano plots to show the differences in expression pattern at the time points studied.ResultsOur results show marked changes in the expression pattern of extracellular matrix, adhesion molecules, chemokines and their receptors with developmental age, particularly in later stages of development. Ten molecules were significantly increased among the LSK populations studied. Our screen identified the upregulation of Col4a1, as well as molecules involved in its degradation (Mmp2, Timp2), with development. Other genes identified were Sell, Tgfbi, and Entpd1. Furthermore, we show that the expression of the chemokines Ccl4, Ccl9, Il18 and the chemokine receptor Cxcr4 increases in LSK cells during development.ConclusionsSeveral genes are upregulated in the LSK population in their transition to the bone marrow microenvironment, increasing at later stages of development. This gene pattern should be emulated by embryonic stem cell-derived hematopoietic progenitors in order to improve their properties for clinical applications such as engraftment.
Highlights
Hematopoietic stem cells (HSCs) follow a genetically programmed pattern of migration during development
This gene pattern should be emulated by embryonic stem cell-derived hematopoietic progenitors in order to improve their properties for clinical applications such as engraftment
Analysis of the frequency of LSK and Long Term-Hematopoietic Stem Cells (LT-HSC) in different microenvironments during development We analyzed the frequency of the LSK population in lineage depleted fetal livers at 14.5 dpc (FL14.5) and 17.5 dpc (FL17.5), in fetal bone marrow at 17.5 dpc (FBM17.5) and in bone marrow from four-week old adult mice (Figure 1a)
Summary
Hematopoietic stem cells (HSCs) follow a genetically programmed pattern of migration during development. Hematopoietic stem cells (HSCs) are the best characterized stem cell population in adult organisms. HSCs lack expression of mature lineage markers (Lin-) and have high expression of Stem cell antigen-1 (Sca-1) and c-Kit receptor tyrosine kinase (stem cell factor receptor) [1]. All these markers define the LSK population (Lin-Sca1+c-Kit+), which contains a heterogeneous mixture of During embryonic development, HSCs follow a defined pattern of migration through different anatomical locations [6,7,8]. LT-HSCs circulating in fetal blood might not possess the appropriate chemokine receptor or adhesion molecule repertoire required for bone marrow homing and migration. The analysis of the expression of these molecules in LT-HSC and LSK populations could shed light into the mechanisms involved during the process of embryonic hematopoietic progenitor migration as well as in the physiological hematopoietic progenitor migration observed in adult organisms [13]
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