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Regulation of hematopoietic and leukemic stem cells by the immune system.

Riether C, Schürch CM, Ochsenbein AF - Cell Death Differ. (2014)

Bottom Line: Leukemic cells express different antigens that are able to activate CD4(+) and CD8(+) T cells.However, the actual interaction of leukemia-specific T cells with LSCs remains ill-defined.In this review, we summarize mechanisms by which the immune system regulates HSCs and LSCs.

View Article: PubMed Central - PubMed

Affiliation: Tumor Immunology, Department of Clinical Research, University of Bern, Bern, Switzerland.

ABSTRACT
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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The hematopoietic stem cell niche. Various cell types including osteoclasts (OCs), osteoblasts (OBs), osteolineage progenitor cells (OLPs), endothelial cells (ECs), mesenchymal stem/stromal cells (MSCs), specialized CXCL12-abundant reticular (CAR) cells and leptin receptor (LEPR)-positive cells contribute to the structure of the BM microenvironment. In addition, this microenvironment is innervated by sympathetic nerves fibers ensheated by nonmyelinating Schwann cells. Hematopoietic stem cells (HSCs) are located in the perivascular region of sinusoids and arterioles in close proximity to MSCs and ECs that regulate HSC maintenance and differentiation through soluble factors such as CXCL12 and angiopoietin-1 or cell contact-dependent signals such vascular cell adhesion molecule-1 (VCAM1). HPC, hematopoietic progenitor cell
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fig2: The hematopoietic stem cell niche. Various cell types including osteoclasts (OCs), osteoblasts (OBs), osteolineage progenitor cells (OLPs), endothelial cells (ECs), mesenchymal stem/stromal cells (MSCs), specialized CXCL12-abundant reticular (CAR) cells and leptin receptor (LEPR)-positive cells contribute to the structure of the BM microenvironment. In addition, this microenvironment is innervated by sympathetic nerves fibers ensheated by nonmyelinating Schwann cells. Hematopoietic stem cells (HSCs) are located in the perivascular region of sinusoids and arterioles in close proximity to MSCs and ECs that regulate HSC maintenance and differentiation through soluble factors such as CXCL12 and angiopoietin-1 or cell contact-dependent signals such vascular cell adhesion molecule-1 (VCAM1). HPC, hematopoietic progenitor cell

Mentions: Many of the functional characteristics of HSCs and LSCs are driven by their surrounding microenvironment in the BM, the so-called HSC niche (Figure 2). The HSC niche has been initially defined as microenvironment that retains HSCs in their localization, avoids differentiation and ensures their stem cell phenotype.33 The functional and anatomical definition as well as the cellular composition of the HSC niche have been highly debated during the last decade. First, osteoblastic lineage cells have been described as critical components of the HSC niche (Figure 2). Bone-forming osteoblasts (OBs) that are located at the endosteal surface of the bone cavities and on trabeculae co-localized with HSCs and regulated the HSC pool size in vivo.34, 35 Furthermore, endosteal osteoclasts influence HSC maintenance and retention in the BM.36, 37 Later, Kiel and co-workers demonstrated that primitive HSCs defined by SLAM markers (CD150+, CD48−) preferentially localize in close proximity to sinusoidal endothelial cells (ECs) but not OBs, identifying sinusoidal blood vessels as HSC niche9 (Figure 2). Clinical observations confirm an important role for ECs in the formation of the HSC niche, as HSCs depend on an intact vasculature for recovery after myeloablation or BM transplantation.38, 39 More recently, perivascular nestin+ mesenchymal stem cells (MSCs) have been defined as central components of the HSC niche that regulate HSCs via the expression of stem cell factor, CXCL12, angiopoietin-1 and vascular cell adhesion molecule-1 (VCAM-1).12 In addition, it was demonstrated that β-adrenergic signals from the sympathetic nervous system mobilize HSCs13 and regulate circadian HSC egress.40


Regulation of hematopoietic and leukemic stem cells by the immune system.

Riether C, Schürch CM, Ochsenbein AF - Cell Death Differ. (2014)

The hematopoietic stem cell niche. Various cell types including osteoclasts (OCs), osteoblasts (OBs), osteolineage progenitor cells (OLPs), endothelial cells (ECs), mesenchymal stem/stromal cells (MSCs), specialized CXCL12-abundant reticular (CAR) cells and leptin receptor (LEPR)-positive cells contribute to the structure of the BM microenvironment. In addition, this microenvironment is innervated by sympathetic nerves fibers ensheated by nonmyelinating Schwann cells. Hematopoietic stem cells (HSCs) are located in the perivascular region of sinusoids and arterioles in close proximity to MSCs and ECs that regulate HSC maintenance and differentiation through soluble factors such as CXCL12 and angiopoietin-1 or cell contact-dependent signals such vascular cell adhesion molecule-1 (VCAM1). HPC, hematopoietic progenitor cell
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4291501&req=5

fig2: The hematopoietic stem cell niche. Various cell types including osteoclasts (OCs), osteoblasts (OBs), osteolineage progenitor cells (OLPs), endothelial cells (ECs), mesenchymal stem/stromal cells (MSCs), specialized CXCL12-abundant reticular (CAR) cells and leptin receptor (LEPR)-positive cells contribute to the structure of the BM microenvironment. In addition, this microenvironment is innervated by sympathetic nerves fibers ensheated by nonmyelinating Schwann cells. Hematopoietic stem cells (HSCs) are located in the perivascular region of sinusoids and arterioles in close proximity to MSCs and ECs that regulate HSC maintenance and differentiation through soluble factors such as CXCL12 and angiopoietin-1 or cell contact-dependent signals such vascular cell adhesion molecule-1 (VCAM1). HPC, hematopoietic progenitor cell
Mentions: Many of the functional characteristics of HSCs and LSCs are driven by their surrounding microenvironment in the BM, the so-called HSC niche (Figure 2). The HSC niche has been initially defined as microenvironment that retains HSCs in their localization, avoids differentiation and ensures their stem cell phenotype.33 The functional and anatomical definition as well as the cellular composition of the HSC niche have been highly debated during the last decade. First, osteoblastic lineage cells have been described as critical components of the HSC niche (Figure 2). Bone-forming osteoblasts (OBs) that are located at the endosteal surface of the bone cavities and on trabeculae co-localized with HSCs and regulated the HSC pool size in vivo.34, 35 Furthermore, endosteal osteoclasts influence HSC maintenance and retention in the BM.36, 37 Later, Kiel and co-workers demonstrated that primitive HSCs defined by SLAM markers (CD150+, CD48−) preferentially localize in close proximity to sinusoidal endothelial cells (ECs) but not OBs, identifying sinusoidal blood vessels as HSC niche9 (Figure 2). Clinical observations confirm an important role for ECs in the formation of the HSC niche, as HSCs depend on an intact vasculature for recovery after myeloablation or BM transplantation.38, 39 More recently, perivascular nestin+ mesenchymal stem cells (MSCs) have been defined as central components of the HSC niche that regulate HSCs via the expression of stem cell factor, CXCL12, angiopoietin-1 and vascular cell adhesion molecule-1 (VCAM-1).12 In addition, it was demonstrated that β-adrenergic signals from the sympathetic nervous system mobilize HSCs13 and regulate circadian HSC egress.40

Bottom Line: Leukemic cells express different antigens that are able to activate CD4(+) and CD8(+) T cells.However, the actual interaction of leukemia-specific T cells with LSCs remains ill-defined.In this review, we summarize mechanisms by which the immune system regulates HSCs and LSCs.

View Article: PubMed Central - PubMed

Affiliation: Tumor Immunology, Department of Clinical Research, University of Bern, Bern, Switzerland.

ABSTRACT
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.

Show MeSH
Related in: MedlinePlus