Figure 1: General differentiation pathway of hemangioblast.

Figure 2.  Cartoon showing ontogeny

Manipulation of common genes and cytokines regulate endothelial and hematopoietic differentiation i.e. Cloche gene in zebrafish (3)and vascular endothelial growth factor receptor 2 (VEGFR-2) in mice (4) regulate both lineages in the early stage of development.  Knocking out stem cell leukemia (SCL) gene will interfere with both hematopoiesis and angiogenesis development in the yolk sac but has greater effects to the latter (5).  Runx1 gene in mice (AML1 in human) has also been found to be essential for differentiating along the erythroid lineage in early hematopoietic development (6).  Cytokines such as thrombopoietin (TPO), fibroblast growth factor (FGF), interleukin-3 (IL-3), erythropoietin (EPO), and hemangiopoietin (HAPO) have been shown to promote differentiation and proliferation along the hematopoietic and endothelial lineages (7).

Hemangioblast research has important implications in clinical applications.  Having the ability to measure the degree of hemangioblast activity with clinical tests could be crucial in patients’ health, both with regards to prognosis and diagnosis.  This could be subsequently used to manage diseases such as sickle cell anemia, myocardial infarction, systemic sclerosis, lymphoma, and breast cancer, as all of these have been linked to increased active endothelial progenitor cell (EPC) levels (1).

In sickle cell anemia, not only are the levels of circulating endothelial cells (CECs) elevated, but the phenotype of CECs also indicates differences between patients with sickle cell anemia, and those without.  The proportion of endothelial cells that are microvascular or express CD36 is higher in patients with sickle cell anemia.  Furthermore, these patients have elevated levels of CECs with surface expression of ICAM-1, VCAM-1, E-selectin, or P-selectin when compared to normal controls (8). 

Both resting and activated CECs are present in elevated levels in breast cancer and lymphoma patients as well.  In addition, after the lymphoma patients achieve complete remission through chemotherapy and after breast cancer patients receive quadrantectomy, CECs were found to decrease.  This supplies a direct correlation between these two types of cancer and CEC levels and can be used in clinical testing (9).

Regulation of hemangioblast activity can be critical as a therapeutic target of angiogenesis and the inhibition of angiogenesis.  The growth of new blood vessels can be used to treat conditions of hypo-proliferation, including myocardial infarction, stroke, and wound healing.  Alternatively, the reduction of new blood vessel growth can be used to treat conditions of hyper-proliferation, such as diabetic retinopathy and cancer (1).

Studies have shown that ex vivo cell therapy which consists of culture-expanded EPC transplantation, successfully promotes neovascularization of ischemic tissues (10).  Furthermore, mononuclear bone marrow cells (BMCs), which contain mesodermal progenitor cells, hematopoietic progenitor cells, and endothelial progenitor cells, may lead to repair of infracted tissue when transplanted during the immediate postinfarction period (11). Additionally, systemically transplanted EPCs have been observed to home to brain tumors with significantly higher specificity as compared to other organs. Therefore, future research is geared towards incorporating EPCs carrying an antiangiogenic gene to retard and destroy tumor vasculature (12).