Molecular Miscommunication Causes Platelet Disorders

A molecular feedback mechanism has been identified that regulates the differentiation of hematopoietic stem cell (HSC) into megakaryocytes and ultimately into platelets.

Megakaryocytes are derived from hematopoietic stem cell precursor cells in the bone marrow. These pluripotent stem cells live in the marrow sinusoids and are capable of producing all types of blood cells depending on the signals they receive. The primary signal for megakaryocyte production is thrombopoietin (leukemia virus oncogene ligand, megakaryocyte growth and development factor) or TPO. Once the cell has completed differentiation and become a mature megakaryocyte, it begins the process of producing platelets. Thrombopoietin plays a role in inducing the megakaryocyte to form small protoplatelet processes.

TPO is a 353-amino acid glycoprotein hormone whose gene is located on chromosome 3p27. TPO is primarily synthesized in the liver but can be made by kidneys, testes, brain, and bone marrow stromal cells. It is essential for the formation of an adequate quantity of platelets. Mice lacking TPO or the TPO receptor (Mpl) have a 90% reduction in circulating platelet number, although the platelets are normal in morphology and function.

Myeloproliferative leukemia virus oncogene (Mpl) is also known as CD110 (Cluster of Differentiation 110). The ligand for Mpl is thrombopoietin. The protein encoded by the Mpl gene, CD110, is a 635 amino acid transmembrane domain, with two extracellular cytokine receptor domains and two intracellular cytokine receptor-box motifs. TPO-R deficient mice were severely thrombocytopenic, emphasizing the important role of CD110 and thrombopoietin in megakaryocyte and platelet formation.

Investigators at the Walter and Eliza Hall Institute (Victoria, Australia) tied the diverse genes and proteins described above into a tight package by their recent work on mice with mutations in the Myb gene. They reported in the November 29, 2010, online edition of the journal Proceedings of the [US] National Academy of Sciences (PNAS) that the blood disorder megakaryocytosis with its increased platelet mass caused reduced circulating TPO concentration and TPO starvation of the stemcell compartment. This imbalance was further exacerbated because these cells additionally exhibited impaired responsiveness to TPO.

HSCs from Myb mutant mice show altered expression of TPO-responsive genes and, like HSCs from TPO and Mpl mutant mice, exhibited increased cycling and a decline in the number of HSCs with age. These findings suggested that disorders of platelet number could have profound effects on the HSC compartment via effects on the feedback regulation of circulating TPO concentration.

"We know that blood stem cells give rise to all the mature blood cells, but the standard assumption was that external factors control blood cell production and the two populations exist in isolation,” said senior author Dr. Doug Hilton, professors of molecular medicine at the Walter and Eliza Hall Institute. "This study shows that the mature cells actually communicate back to the stem cells, changing their gene expression and influencing their behavior. What we would like to do is to determine whether some of these stem cell failures are due to miscommunication between mature blood cells and stem cells, with the possibility of finding new ways to treat these disorders down the track.”

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Walter and Eliza Hall Institute