A Systems Biology Approach for Defining the Molecular Framework of the Hematopoietic Stem Cell Niche

Abstract

Despite progress in identifying the cellular composition of hematopoietic stem/progenitor cell (HSPC) niches, little is known about the molecular requirements of HSPC support. To address this issue, we used a panel of six recognized HSPC-supportive stromal lines and less-supportive counterparts originating from embryonic and adult hematopoietic sites. Through comprehensive transcriptomic meta-analyses, we identified 481 mRNAs and 17 microRNAs organized in a modular network implicated in paracrine signaling. Further inclusion of 18 additional cell strains demonstrated that this mRNA subset was predictive of HSPC support. Our gene set contains most known HSPC regulators as well as a number of unexpected ones, such as Pax9 and Ccdc80, as validated by functional studies in zebrafish embryos. In sum, our approach has identified the core molecular network required for HSPC support. These cues, along with a searchable web resource, will inform ongoing efforts to instruct HSPC ex vivo amplification and formation from pluripotent precursors.

Thymic Mesenchymal Cells Have a Distinct Transcriptomic Profile

“…7H). These data suggest that although MCs from all tested tissues constitutively express genes predicted to support HSCs, these genes are expressed at higher levels in MCs from organs that harbor hematolymphoid progenitors with self-renewal potential (i.e., the bone and thymus) (31,61,62 (28). We found that genes coding for these seven receptors were expressed (RPKM .2) in at least one population of hematopoietic progenitors (Fig.…”

“…The independent dataset containing genes predicted to support hematopoietic stem cells (HSCs) and identified as core genes operative in site of hematopoiesis originated from Charbord et al (31). The original list of 481 genes was filtered to retrieve only the 309 genes upregulated in HSCsupportive mesenchymal cell lines compared with less-supportive mesenchymal cell lines (Supplemental Table I).…”

“…7G). To further explore the relationship between MCs and HSCs, we used a list of 309 genes expressed at relatively high levels in HSC-supportive mesenchymal cell lines and identified as core genes operative in site of hematopoiesis (31). When we compared the expression of these 309 genes in our three MC populations and in thymocytes, we made two observations: 1) these 309 genes were expressed at higher levels in the three MC populations than in thymocytes; and 2) they were expressed at higher levels in bone and thymic MCs than in skin MCs (p , 0.001; Fig.…”

The European Hematology Association Roadmap for European Hematology Research: a consensus document

“…Mouse models and systems biology approaches are beginning to provide insight into the molecular differences between embryonic, fetal, and adult hematopoietic cells and their specific developmental microenvironments. 43 Considerable advances have been made regarding the cellular complexity of the bone marrow HSC niche, but very little is known about specific cellular components and the molecular signatures of the cells within the HSC supportive niches of the developing embryo.…”

“…Detailed characterization of the properties of MSCs will rely on the development of markers to isolate relevant subsets of human MSCs and understand their HSC-supporting and regulatory properties at the anatomical and functional levels. 43 Understanding the role of mesenchymal elements in human disease: future work will uncover the complexity of HSCstroma reciprocal regulation in normal and pathological settings. Recent intravital microscopy studies showed altered physical interaction between HSCs and stroma during infection.…”