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HEMANGIOBLAST STEM CELLS

Lay Summary

 

Introduction:

       Stem cells have been investigated for decades as scientists began to question the developmental pathways of embryos in various animal models, including humans. P.D.F. Murray in 1932 first coined the term “hemangioblast” through his dissections of chick embryos. He discovered that there were cells in the chick embryos that were capable of producing blood cells and the cells of the blood vessels 18. In the early 1960s, Till and McCulloch performed the historical experiment where they transplanted bone marrow cells from a healthy donor to a mouse whose immune system had been diminished due to radiation. The resulting immune system reconstitution led to the discovery of hematopoietic cells, which are capable of producing immune system and circulatory system cells 13.
Fertilization is followed by the growth of the embryo. Hemangioblasts produce blood vessels known as endothelial cells, and blood cells known as hematopoietic cells 4. There is a parallel physiological development of endothelial and hematopoietic cells because an efficient transport system is required along with transport structures for further successful development. Since the blood cells and blood vessels develop together and close to each other, they are thought to share a common progenitor, the hemangioblast 3.

Basic Biology  & Development:

      Hemangioblasts can be found in the earliest developmental areas of the embryo. Pluripotent cells, cells that have the ability to form all cells of the body, give rise to the primitive hemangioblast. Figure 1 at the end of the paper summarizes the developmental plan of hemangioblasts, while Figure 2 details the pathway of hemangioblast growth through the embryo. Hemangioblasts are observed in high concentrations in the placenta, the aorta-gonad-mesonephros (AGM), and the para-aortic splanchopleura 12, 17. The cells proceed from the AGM to the fetal liver and fetal bone marrow, and finally to the adult bone marrow to be developed as immune system cells. Hemangioblasts might function throughout the adult life as a source of blood cells and blood vessels 15.
Hemangioblasts give rise to erythrocytes, lymphocytes, granulocytes, and lymphocytes; these cells can further produce other cells of the immune and circulatory system, such as red blood cells, white blood cells, platelets, natural killer cells, macrophages, etc.  Cells of the blood vessels are also produced from hemangioblasts. Hemangiopoietin is the human hemangioblast growth factor that regulates the production of such lineages during the development of the blood island 3,18. The blood island is a cluster of blood vessel cells and blood cells. The allantois or the placenta is involved in respiration, excretion, nutrient exchange, and development of bone 14. It has been implicated as a site for hemangioblasts in birds. Grafts between chick and quail embryos provide evidence for the allantois as housing progenitors for blood and blood vessel cells, since red blood cells were produced along with the proper vascular network 7.
      The microenvironment of hemangioblasts is very important in development. Low oxygen levels are favored for rapid development and growth of hemangioblast to produce its multiple lineages. Nitric oxide (NO) can also affect the activity of hemangioblasts progenies by regulating blood vessel formation during development and wound healing 9. 

Relevance to Medicine & Disease:

      Hemangioblasts could be used as diagnostic cells for multiple diseases involving growth abnormalities of hematopoietic and endothelial cells. Patients with Down’s syndrome have multiple developmental deficits, including too much production of certain immune system cells that can later progress to leukemia 3. Since hemangioblasts are required for the formation of immune system cells, medications could developed to target the immune system cell precursors, thereby controlling leukemia. Severe thrombocytopenia is another disorder that results from too few blood cells. Since the patients have very low platelet and red blood cell counts, the fetus can survive the pregnancy and birth with help from mother’s body, but post-delivery survival is rare because the body is unable to survive on its own 3. Hemangioblasts could be studied in developing embryos to examine proper growth, so that diagnoses of such disorders can be given ahead of time rather than after the disease has had significant impact.

      Hemangiopoietin could be used in cases of HSC transplantation 18. Injections of hemangiopoietin would ensure proper growth of the hemangioblasts into target tissues for blood vessel growth and stimulate blood synthesis. Anti-angiogenic therapy could be used to treat disorders, such as breast cancer and systemic sclerosis, characterized by too much branching of the blood vessels. Therapeutic angiogenesis could used to treat lack of growth in cases of would healing, heart attacks, and stroke to stimulate blood vessel branching and blood cell production. Hemangioblasts could even be grown in lab to produce red blood cells so that clean and disease-free blood could be used to administer to patients, with much lower medical costs and less chances of rejection after blood perfusions 18.

      There are naturally occurring cases of blood vessel growth in the body: some that are beneficial and some that are harmful. The advantageous instances of growth occur during menstruation, would healing, heart attacks, and brain injury 18. There are even greater numbers of instances where it is harmful for growth to occur, such as cancer, diabetic retinopathy, rheumatoid arthritis, arteriosclerosis, sickle- cell anemia, systemic sclerosis, lymphoma, and breast cancer 18. 
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References:

  1. Chan RJ, Hromas R, Yoder MC. The role of Hex in hemangioblast and hematopoietic development. Meth Mol Biol 2006;330:123-33.
  2. Glasker S, Li J, Xia JB, Okamoto H, Zeng W, Lonser RR, Zhuang Z, Oldfield EH, Vortmeyer AO. Hemangioblastomas share protein expression with embryonal hemangioblast progenitor cell. Cancer Res 2006;66:4167-72.
  3. Tober JM, Koniski A, McGrath KE, Vemishetti R, Emerson R, de Mesy-Bentley KK, Waugh R, Palis J. The megakaryocyte lineage originates from hemangioblast precursors and is an integral component both of primitive and of definitive hematopoiesis. Blood 2007;109:1433-41.
  4. Zafonte BT, Liu S, Lynch-Kattman M, Torregroza I, Benvenuto L, Kennedy M, Keller G, Evans T. Smad1 expands the hemangioblast population within a limited developmental window. Blood 2006;109:516-23.
  5. Perlingeiro RC, Kyba M, Bodie S, Daley GQ. A Role for Thrombopoietin in Hemangioblast Development. Stem Cells 2003;21:272-280
  6. Choi K. The Hemangioblast:  a common progenitor of hematopoietic and endothelial cells. J Hematother Stem Cell Res 2002;11:91-101
  7. Caprioli A, Minko K, Drevon C, Eichmann A, Dieterlen-Lievre F, Jaffredo T. Hemangioblast commitment in the avian allantois: cellular and molecular aspects. Dev Biol 2001;238:64-78.
  8. Ramirez-Bergeron DL, Runge A, Dahl KD, Fehling HJ, Keller G, Simon MC. Hypoxia affects mesoderm, and enhances hemangioblasts specification during early development. Dev 2004;131:4623-34
  9. Guthrie SM, Curtis LM, Mames RN, Simon GG, Grant MB, Scott EW. The nitric oxide pathway modulates hemangioblast activity of adult hematopoietic stem cells. Blood 2005;105:1916-22.
  10. Grant MB, May WS, Caballero S, Brown GA, Guthrie SM, Mames RN, Byrne BJ, Vaught T, Spoerri PE, Peck AB, Scott EW. Adult hematopoietic stem cells provide functional hemangioblast activity during retinal neovascularization. Nat Med 2002;8:607-12.
  11. Park C, Ma YD, Choi K. Evidence for the hemangioblast. Exp Hematol 2005;33:965-70.
  12. Bollerot K, Pouget C, Jaffredo T. The embryonic origins of hematopoietic stem cells: a tale of hemangioblast and hemogenic endothelium. Acta Path Micro et Immuno Scand 2005;113:790-803.
  13. Till JE, McCulloch E. A direct measurement of radiation sensitivity of normal mouse bone marrow cells. Radiat Res 1961;14:213-22
  14. Jaffredo T, Bollerot K, Sugiyama D, Gautier R, Drevon C. Tracing the hemangioblast during embryogenesis: developmental relationships between endothelial and hematopoietic cells. Int J Dev Biol 2005;49:269-77.
  15. Pelosi E, Valtieri M, Coppola S, Botta R, Gabbianelli M, Lulli V, Marziali G, Masella B, Muller R, Sgadari C, Testa U, Bonanno G, Peschle C. Identification of the hemangioblast in postnatal life. Blood 2002;100:3203-8.
  16. Guo Y, Chan R, Ramsey H, Li W, Xie X, Shelley WC, Martinez-Barbera JP, Bort B, Zaret K, Yoder M, Hromas R. The homeoprotein Hex is required for hemangioblast differentiation. Blood 2003;102:2428-35.
  17. Forrai A, Robb L. The hemangioblast--between blood and vessels. Cell Cycle 2003;2:86-90.
  18. Cogle CR & Scott EW. The Hemangioblast: Cradle to clinic. Exp Hematol 2004;32:885-90.

Acknowledgements:
This review was prepared by the following graduate students in the Stem Cell Biology Class, Graduate School of Biomedical Sciences (Fall 2006), University of Medicine and Dentistry of New Jersey:

Shweta Rane, Nidhi Shah (in alphabetical order)

Teaching Assistant: Katherine Liu