Identification of immune-activated hematopoietic stem cells.
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ABSTRACT:
SUBMITTER: Bujanover N
PROVIDER: S-EPMC6127088 | biostudies-literature | 2018 Sep
REPOSITORIES: biostudies-literature
Publications
Identification of immune-activated hematopoietic stem cells.
Bujanover Nir N Goldstein Oron O Greenshpan Yariv Y Turgeman Hodaya H Klainberger Amit A Scharff Ye'ela Y Gazit Roi R
Leukemia 20180724 9
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Project description:Identification of immune-activated Hematopoietic Stem Cells
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Project description:Splenic hematopoiesis is crucial to the pathogenesis of diseases including myocardial infarction and atherosclerosis. The spleen acts as a reservoir of myeloid cells, which are quickly expelled out in response to acute inflammation. In contrast to the well-defined bone marrow hematopoiesis, the cellular and molecular components sustaining splenic hematopoiesis are poorly understood. Surprisingly, we found that, unlike quiescent bone marrow hematopoietic stem cells (HSC), most of splenic HSC are in the G1 phase in C57BL/6 mice. Moreover, splenic HSC were enriched for genes involved in G0-G1 transition and expressed lower levels of genes responsible for G1-S transition. These data indicate that, at steady state, splenic HSC are pre-activated, which may expedite their cell cycle entry in emergency conditions. Consistently, in the acute phase of septic shock induced by LPS injection, splenic HSC entered the S-G2-M phase, whereas bone marrow HSC did not. Mobilization and transplantation experiments displayed that bone marrow HSC, once in the spleen, acquired cell cycle status similar to splenic HSC, strongly suggesting that the splenic microenvironment plays an important role in HSC pre-activation. In addition, we found that myeloid translocation gene 16 (Mtg16) deficiency in C57BL/6 mice resulted in significantly increased S-G2-M entry of splenic but not bone marrow HSC, suggesting that Mtg16 is an intrinsic negative regulator of G1-S transition in splenic HSC. Altogether, this study demonstrates that compared to bone marrow, splenic HSC are in a pre-activated state, which is driven by extracellular signals provided by splenic microenvironment and HSC intrinsic factor Mtg16.
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Project description:To investigate chronic lymphocytic leukemia (CLL)-initiating cells, we assessed NOTCH1 mutation/expression in hematopoietic stem cells (HSCs). In NOTCH1-mutated CLL, we detected subclonal mutations in 57% CD34+/CD38- HSCs. NOTCH1 mutation was present in 66% CD34+/CD38+ progenitor cells displaying an increased mutational burden compared to HSCs. Flow cytometric analysis revealed significantly higher NOTCH1 activation in CD34+/CD38- and CD34+/CD38+ cells from CLL patients, regardless NOTCH1 mutation compared to healthy donors. Activated NOTCH1 resulted in overexpression of the NOTCH1 target c-MYC. We conclude that activated NOTCH1 is an early event in CLL that may contribute to aberrant HSCs in this disease.
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Project description:Hematopoietic stem cells (HSCs) are rare, multipotent cells that generate via progenitor and precursor cells of all blood lineages. Similar to normal hematopoiesis, leukemia is also hierarchically organized and a subpopulation of leukemic cells, the leukemic stem cells (LSCs), is responsible for disease initiation and maintenance and gives rise to more differentiated malignant cells. Although genetically abnormal, LSCs share many characteristics with normal HSCs, including quiescence, multipotency and self-renewal. Normal HSCs reside in a specialized microenvironment in the bone marrow (BM), the so-called HSC niche that crucially regulates HSC survival and function. Many cell types including osteoblastic, perivascular, endothelial and mesenchymal cells contribute to the HSC niche. In addition, the BM functions as primary and secondary lymphoid organ and hosts various mature immune cell types, including T and B cells, dendritic cells and macrophages that contribute to the HSC niche. Signals derived from the HSC niche are necessary to regulate demand-adapted responses of HSCs and progenitor cells after BM stress or during infection. LSCs occupy similar niches and depend on signals from the BM microenvironment. However, in addition to the cell types that constitute the HSC niche during homeostasis, in leukemia the BM is infiltrated by activated leukemia-specific immune cells. Leukemic cells express different antigens that are able to activate CD4(+) and CD8(+) T cells. It is well documented that activated T cells can contribute to the control of leukemic cells and it was hoped that these cells may be able to target and eliminate the therapy-resistant LSCs. However, the actual interaction of leukemia-specific T cells with LSCs remains ill-defined. Paradoxically, many immune mechanisms that evolved to activate emergency hematopoiesis during infection may actually contribute to the expansion and differentiation of LSCs, promoting leukemia progression. In this review, we summarize mechanisms by which the immune system regulates HSCs and LSCs.
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Project description:Hematopoietic stem cells (HSCs) cultured outside the body are the fundamental component of a wide range of cellular and gene therapies. Recent efforts have achieved > 200-fold expansion of functional HSCs, but their molecular characterization has not been possible since the majority of cells are non-HSCs and single cell-initiated cultures have substantial clone-to-clone variability. Using the Fgd5 reporter mouse in combination with the EPCR surface marker, we report exclusive identification of HSCs from non-HSCs in expansion cultures. By directly linking single-clone functional transplantation data with single-clone gene expression profiling, we show that the molecular profile of expanded HSCs is similar to proliferating fetal HSCs and reveals a gene expression signature, including Esam, Prdm16, Fstl1, and Palld, that can identify functional HSCs from multiple cellular states. This "repopulation signature" (RepopSig) also enriches for HSCs in human datasets. Together, these findings demonstrate the power of integrating functional and molecular datasets to better derive meaningful gene signatures and opens the opportunity for a wide range of functional screening and molecular experiments previously not possible due to limited HSC numbers.
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