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Selected factors influencing angiogenesis and hematopoietic niche

Abstract Angiogenesis is the vital, multistage process in which new blood vessels are created by sprouting from pre-existing vessels. It takes part in carcinogenesis and contributes to progression, metastases, and dissemination of neoplastic disease. In the bone marrow, angiogenesis influences the hematopoietic stem cells (HSC) proliferation, differentiation, and maintenance of normal hematopoiesis under both physiological and stress conditions. The bone marrow niche contains different types of cells, including macrophages, osteoblasts, mesenchymal stem cells, endothelial progenitors, and endothelial cells. All of these interact and form a unique microenvironment necessary for the appropriate function, and preservation of HSC in the quiescent state, and take a major part in the process of mobilization to peripheral blood and homing after transplantation. Cytokines active in the hematopoietic niche as well as miRNAs regulating hemato- poiesis, and angiogenesis have a significant influence on processes occurring in the bone marrow. The aim of this review was to present selected proteins, and molecules associated with angiogenesis as well as bone marrow niche processes: VEGF, ANGPT1, ANGPT2, MMP-9, SDF-1, miRNA-15a, miRNA-16, miRNA-126, miRNA-146a, and miRNA-223.

(sKitL) form bone marrow stromal cells, which promotes the transfer of EC and HSC from quiescence state to proliferation [47]. A smooth transition of hematopoietic stem cells through the blood vessel wall is necessary for their effective mobilization from the bone marrow niche and engraftment after transplantation. MMP-9 allows this transmigration through the partial degradation of the sub-endothelial basement membrane, composed primarily of type IV collagen, which results in effective diapedesis [43]. IL-10 activates tissue inhibitor of metalloproteinases 1 (TIMP-1), which downregulates expression of MMP-9 and promotes HSC adhesion to the bone marrow osteoblastic niche and hematological reconstitution [48]. In HSC mobilization, G-CSF stimulates the release of proteolytic enzymes from neutrophils, including metalloproteinases and leads to profound changes in the HSC microenvironment [49]. G-CSF exerts its activity not only by binding with its receptor on neutrophils and HSCs but also via an indirect mechanism since the presence of a G-CSF receptor is not solely required for mobilization [49]. During G-CSF-mediated mobilization neutrophil degranulation occurs leading to upregulation of the matrix metalloproteases [50].
The proteolytic environment created by MMP-9, involving G-CSF administration after transplantation or during mobilization, adjusts the level of vascular cell adhesion molecule 1 (VCAM-1) which significantly influences the effectiveness of the release of HSC from bone marrow as well as their homing after HSCT [46,50,51].
By signaling cross-talk with VEGF, MMP-9 regulates EC migration, endothelium permeability, formation of new blood vessels and metastasis of cancer cells [45].

SDF-1
Stromal cell-derived factor 1 (SDF-1, CXCL12) is a key protein in the migration and proliferation of cells that have a CXCR4 receptor on their surface, e.g. HSC, EC, and cancer cells [52]. Upregulated expression of CXCR4 is a predictor of poor prognosis in many malignancies. In the course of AML and B-cell ALL, overexpression of CXCR4 on CD34 positive cells is observed [53,54]. The interaction between CXCR4 and SDF-1 ligand causes homing of the leukemic cells in a protective microenvironment of bone marrow niche, resulting in resistance to chemotherapy [53,54].
The SDF-1/CXCR4 signaling pathway plays an important role in the mobilization of hematopoietic stem cells from the bone marrow niche to the peripheral blood [55]. When used in the mobilization of HSC, G-CSF interferes with the SDF-1/CXCR4 signaling pathway, reducing the adhesion of HSC to the hematopoietic niche [55][56][57].
Chemotherapy and proinflammatory cytokines cause a short-term increase in the concentration of SDF-1 in the bone marrow. Expression of this chemokine facilitates HSC homing after transplantation. SDF-1 promotes cell survival during stress and stimulates osteoclasts to produce MMP-9 [58].
The bone marrow microenvironment, containing endothelial cells, contributes to proper hematopoietic stem cell function, including regeneration after injury caused by chemotherapy. Myelosuppression resulting from cytostatic agents is accompanied by destruction of bone marrow vasculature; microvessels are then reconstructed with the recovery of hematopoiesis. Moreover, the angiogenic factors including ANGPT1, ANGPT2, and VEGF play supportive roles in the process of mobilization of CD34+ cells to the peripheral blood.
All of those observations indicate an important function of the microvasculature in the migration of hematopoietic progenitors.
The expression of cytokines active in angiogenesis as well as those responsible for maintenance of the homeostasis in hematopoietic niche is modulated by miRNAs.
These molecules participate in the regulation of vital processes such as cell proliferation, differentiation, and apoptosis [65][66][67][68][69]. Targeting the bone marrow niche gene pathways and cytokines certain miRNAs can modulate angiogenesis, mobilization of HSC and homing after transplantation [70][71][72]. The role of selected miRNAs in hematopoiesis is presented in table I.
MiRNA-16 is involved in normal erythropoiesis, while deregulation of this miRNA contributes to abnormal erythroid lineage in polycythemia vera [72]. Apart from the influence on the development of cancer, miRNA-15a/-16 is associated with chemoresistance. It has been shown that low level of these miRNAs reduces apoptosis, increases proliferation of tumor cells and angiogenesis [78]. Downregulation of the miRNA-15a/-16 level inversely correlates with the expression of oncogenes BCL-2 and BCL-XL in myeloma cells and neoplastic B cells [76,79]. Deregulation of miRNA-15a/-16 expression may affect the efficacy of chemotherapy. The resistance to apoptosis, induced by a low level of miRNA-15a/-16 reduces the activity of cytarabine [80].

miRNA-126
Cytokines and adhesion molecules regulate the migration of HSC between the hematopoietic niche and the peripheral blood.

G-CSF-stimulation during mobilization of CD34 positive cells induces
accumulation of microvesicles containing miRNA-126 and leads to downregulation of VCAM-1 expression on bone marrow cells surface [81,82]. VCAM-1 downregulation increases the hematopoietic and progenitor stem cells release from the bone marrow niche and suppresses homing after HSCT.
MiRNA-126 can influence the expression of ZFP91 gene in hematopoietic progenitor cells (HPC) which results in modulation of CD34+ cells proliferation, tumorigenesis as well as apoptosis [83]. ZFP91 gene promotes the proliferation of tumor cells through transcription factor NF-κB mediated activation of HIF-1α [84].

miRNA-146a
MiRNA-146a is an important molecule influencing inflammation and tumorigenesis. Expression of this miRNA is induced by the NF-κB protein complex, which plays a significant role in inflammatory response [90]. MiRNA-146a regulates mobilization of HSC as well as their homing after bone marrow transplantation [90][91][92][93]. Previous research has shown that under the influence of G-CSF, expression of CXCR4 chemokine receptor mRNA and protein in AML cells was decreased while the level of miRNA-146a was increased [94]. MiRNA-146a affects the CXCR4 mRNA, which leads to disruption of the SDF-1/ CXCR4 signaling pathway. It results in more efficient mobilization of HSCs, and slower homing [94]. Urocinase-type plasminogen activator receptor (uPAR), known to be modulated by miRNA-146a, by binding vitronectin is involved in extracellular matrix degradation, cell adhesion, and migration. It also allows cross-talk with CXCR4.
Through downregulating of superoxide dismutase 2 enzyme (SOD2) expression, miRNA-146a increases apoptosis and sensitivity to chemotherapy of cancer cells, by enhancement of reactive oxygen species (ROS) generation [97].
MiRNA-223 stimulates granulopoiesis, erythroid, and megakaryocyte differentiation via targeting NFI-A, IGF-1R, and LMO2 genes. It is also crucial for homeostasis of mature neutrophils, and limits inflammation [103,104]. Using transcription factors (TF) miRNA-223 is associated with regulation of network-specific signaling for HPC and differentiation of hematopoietic lines. MiRNA-223 is responsible for the appropriate development, and maturation of myeloid progenitors to granulocytic, erythroid, as well as monocyte/macrophage lines [103,105].

High-level expression of granulocyte-macrophage progenitors (GMP)
is linked to a deficiency of miRNA-223 in mice [107]. In contrast, the progress of human granulopoiesis and progenitor cells differentiation is associated with higher expression of this molecule [104,107].
MiRNA-223 is involved in neoplastic cells development. This miRNA modulates apoptosis by targeting oncogene BCL-2 and insulin

Authors' contributions/Wkład autorów
The author and co-authors were responsible for the substantive part of the review and linguistic correction.

Conflict of interest/Konflikt interesu
We declare no conflict of interest.

Financial support/Finansowanie
The review did not require financial support.

Ethics/Etyka
The work described in this article has been carried out in accordance  [27] Saharinen P, Alitalo K. The yin, The yang, and the angiopoietin-1.