Parsing the niche code: The molecular mechanisms governing hematopoietic stem cell adhesion and differentiation

Haematologica (Impact Factor: 5.81). 11/2009; 94(11):1477-81. DOI: 10.3324/haematol.2009.013730
Source: PubMed

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    • "They are endowed with multilineage differentiation potential toward mesodermal cell lineages and extensive immunomodulatory properties. MSCs actively proliferate in some tissues, but remain quiescent in others [29]. Three main criteria have been identified by the International Society of Cellular Therapy to define MSCs: (i) adhesion to plastic, (ii) expression of specific immunophenotypic marker combinations (CD73, CD90, and CD105), accompanied by lack of expression of hematopoietic markers (CD14, CD34, and CD45) and class II major histocompatibility complex (MHC) molecules; (iii) capability of differentiating into mesodermal lineages (adipocytes, cardiomyocytes, osteoblasts, and chondrocytes) [30] [31]. "
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    ABSTRACT: Hematopoietic stem cells (HSCs) reside in bone marrow niches and give rise to hematopoietic precursor cells (HPCs). These have more restricted lineage potential and eventually differentiate into specific blood cell types. Bone marrow also contains mesenchymal stromal cells (MSCs), which present multilineage differentiation potential toward mesodermal cell types. In bone marrow niches, stem cell interaction with the extracellular matrix is mediated by integrin receptors. Ion channels regulate cell proliferation and differentiation by controlling intracellular Ca(2+), cell volume, release of growth factors, and so forth. Although little evidence is available about the ion channel roles in true HSCs, increasing information is available about HPCs and MSCs, which present a complex pattern of K(+) channel expression. K(+) channels cooperate with Ca(2+) and Cl(-) channels in regulating calcium entry and cell volume during mitosis. Other K(+) channels modulate the integrin-dependent interaction between leukemic progenitor cells and the niche stroma. These channels can also regulate leukemia cell interaction with MSCs, which also involves integrin receptors and affects the MSC-mediated protection from chemotherapy. Ligand-gated channels are also implicated in these processes. Nicotinic acetylcholine receptors regulate cell proliferation and migration in HSCs and MSCs and may be implicated in the harmful effects of smoking.
    Full-text · Article · Aug 2012
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    • "Other factors also contribute to HSC localization to the BM either in conjunction with CXCR4, such as prostaglandin E2 (PGE2) and the neuronal guidance protein Robo4 (Hoggatt et al., 2009; Smith-Berdan et al., 2011), or independently from CXCR4 like c-Kit, the calcium-sensing receptor (CaR), and the transcription factor Egr1 (Christensen et al., 2004; Adams et al., 2006; Min et al., 2008). Thereafter, HSCs remain anchored in the BM niche by complex integrindependent mechanisms (Scott et al., 2003; Forsberg and Smith- Berdan 2009), though small numbers of HSCs will periodically migrate from the BM into the circulation and back for short periods of time under homeostatic conditions, perhaps as a form of immunosurveillance (Massberg et al., 2007; Bhattacharya et al., 2009). Taken together, these data underscore the dynamic nature of hematopoietic development from embryogenesis through adulthood. "
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    ABSTRACT: Hematopoietic stem cells (HSCs) give rise to all lineages of blood cells. Because HSCs must persist for a lifetime, the balance between their proliferation and quiescence is carefully regulated to ensure blood homeostasis while limiting cellular damage. Cell cycle regulation therefore plays a critical role in controlling HSC function during both fetal life and in the adult. The cell cycle activity of HSCs is carefully modulated by a complex interplay between cell-intrinsic mechanisms and cell-extrinsic factors produced by the microenvironment. This fine-tuned regulatory network may become altered with age, leading to aberrant HSC cell cycle regulation, degraded HSC function, and hematological malignancy.
    Full-text · Article · Nov 2011 · The Journal of Cell Biology
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    • "At the endosteal surface [8], which is the interface between bone and the BM, specialized osteoblasts represent the main components of HSC niche [9], [10]. It has been proposed that this heterogeneous group of cells regulates HSC survival, self-renewal, migration, differentiation, and quiescence [11], [12] through several soluble factors and their receptors such as angiopoietin/Tie2 [13], osteopontin [14], [15] and Ca2+/CaR [16], as well as direct contact through extracellular matrix and cell surface proteins [17], [18], such as integrins [19], [20]. HSC engraftment is a multistep process involving homing, transmarrow migration, and lodging within the BM niche [15], all of which is controlled by adhesion molecules, soluble ligands and their receptors [3]. "
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    ABSTRACT: Hematopoietic stem cell (HSC) homeostasis in the adult bone marrow (BM) is regulated by both intrinsic gene expression products and interactions with extrinsic factors in the HSC niche. GRP94, an endoplasmic reticulum chaperone, has been reported to be essential for the expression of specific integrins and to selectively regulate early T and B lymphopoiesis. In GRP94 deficient BM chimeras, multipotent hematopoietic progenitors persisted and even increased, however, the mechanism is not well understood. Here we employed a conditional knockout (KO) strategy to acutely eliminate GRP94 in the hematopoietic system. We observed an increase in HSCs and granulocyte-monocyte progenitors in the Grp94 KO BM, correlating with an increased number of colony forming units. Cell cycle analysis revealed that a loss of quiescence and an increase in proliferation led to an increase in Grp94 KO HSCs. This expansion of the HSC pool can be attributed to the impaired interaction of HSCs with the niche, evidenced by enhanced HSC mobilization and severely compromised homing and lodging ability of primitive hematopoietic cells. Transplanting wild-type (WT) hematopoietic cells into a GRP94 null microenvironment yielded a normal hematology profile and comparable numbers of HSCs as compared to WT control, suggesting that GRP94 in HSCs, but not niche cells, is required for maintaining HSC homeostasis. Investigating this, we further determined that there was a near complete loss of integrin α4 expression on the cell surface of Grp94 KO HSCs, which showed impaired binding with fibronectin, an extracellular matrix molecule known to play a role in mediating HSC-niche interactions. Furthermore, the Grp94 KO mice displayed altered myeloid and lymphoid differentiation. Collectively, our studies establish GRP94 as a novel cell intrinsic factor required to maintain the interaction of HSCs with their niche, and thus regulate their physiology.
    Full-text · Article · Jul 2011 · PLoS ONE
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