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Credit: Walter and Eliza Hall
Institute of Medical Research
Investigators say they’ve determined how thrombopoietin (TPO) stimulates platelet production, and their findings may have implications for myeloproliferative neoplasms.
Researchers have long known that TPO is responsible for signaling cells in the bone marrow to produce platelets, but precisely which cells respond to TPO’s signals has been unclear.
Now, a group of investigators studying the TPO receptor Mpl have pinpointed those cells and made an unexpected discovery.
“Thrombopoietin did not directly stimulate the platelet’s ‘parent’ cells—the megakaryocytes—to make more platelets,” said study author Ashley Ng, PhD, of the Walter and Eliza Hall Institute of Medical Research in Victoria, Australia.
“Thrombopoietin signals actually acted on stem cells and progenitor cells, several generations back.”
Dr Ng and his colleagues reported these findings in PNAS.
The researchers had generated mice that express the Mpl receptor normally on stem and progenitor cells but lack expression on megakaryocytes and platelets. And these mice exhibited “profound” megakaryocytosis and thrombocytosis, as well as “remarkable” expansion of megakaryocyte-committed and multipotent progenitor cells.
“The progenitor and stem cells in the bone marrow began massively expanding and effectively turned the bone marrow into a megakaryocyte-making machine,” Dr Ng said.
Furthermore, although the progenitor cells showed signs of chronic TPO overstimulation, TPO levels were normal. This suggests that stem and progenitor cells expressing Mpl were responsible for TPO clearance, according to the investigators.
“Our findings support a theory whereby megakaryocytes and platelets control platelet numbers by ‘mopping up’ excess amounts of thrombopoietin in the bone marrow,” Dr Ng said. “In fact, we show this ‘mopping up’ action is absolutely essential in preventing blood disease where too many megakaryocytes and platelets are produced.”
So the researchers believe these findings will have implications for myeloproliferative neoplasms, particularly essential thrombocythemia.
“[P]revious studies have shown megakaryocytes and platelets in people with essential thrombocythemia have fewer Mpl receptors, which fits our model for excessive platelet production,” Dr Ng said.
To add support to their model, the investigators compared the progenitor cells responsible for overproducing megakaryocytes in their model to progenitor cells from patients with essential thrombocythemia. Both sets of cells showed a TPO stimulation signature.
“We think this study now provides a comprehensive model of how thrombopoietin controls platelet production,” Dr Ng said, “and perhaps gives some insight into the biology and mechanism behind specific myeloproliferative disorders.” 
Credit: Walter and Eliza Hall
Institute of Medical Research
Investigators say they’ve determined how thrombopoietin (TPO) stimulates platelet production, and their findings may have implications for myeloproliferative neoplasms.
Researchers have long known that TPO is responsible for signaling cells in the bone marrow to produce platelets, but precisely which cells respond to TPO’s signals has been unclear.
Now, a group of investigators studying the TPO receptor Mpl have pinpointed those cells and made an unexpected discovery.
“Thrombopoietin did not directly stimulate the platelet’s ‘parent’ cells—the megakaryocytes—to make more platelets,” said study author Ashley Ng, PhD, of the Walter and Eliza Hall Institute of Medical Research in Victoria, Australia.
“Thrombopoietin signals actually acted on stem cells and progenitor cells, several generations back.”
Dr Ng and his colleagues reported these findings in PNAS.
The researchers had generated mice that express the Mpl receptor normally on stem and progenitor cells but lack expression on megakaryocytes and platelets. And these mice exhibited “profound” megakaryocytosis and thrombocytosis, as well as “remarkable” expansion of megakaryocyte-committed and multipotent progenitor cells.
“The progenitor and stem cells in the bone marrow began massively expanding and effectively turned the bone marrow into a megakaryocyte-making machine,” Dr Ng said.
Furthermore, although the progenitor cells showed signs of chronic TPO overstimulation, TPO levels were normal. This suggests that stem and progenitor cells expressing Mpl were responsible for TPO clearance, according to the investigators.
“Our findings support a theory whereby megakaryocytes and platelets control platelet numbers by ‘mopping up’ excess amounts of thrombopoietin in the bone marrow,” Dr Ng said. “In fact, we show this ‘mopping up’ action is absolutely essential in preventing blood disease where too many megakaryocytes and platelets are produced.”
So the researchers believe these findings will have implications for myeloproliferative neoplasms, particularly essential thrombocythemia.
“[P]revious studies have shown megakaryocytes and platelets in people with essential thrombocythemia have fewer Mpl receptors, which fits our model for excessive platelet production,” Dr Ng said.
To add support to their model, the investigators compared the progenitor cells responsible for overproducing megakaryocytes in their model to progenitor cells from patients with essential thrombocythemia. Both sets of cells showed a TPO stimulation signature.
“We think this study now provides a comprehensive model of how thrombopoietin controls platelet production,” Dr Ng said, “and perhaps gives some insight into the biology and mechanism behind specific myeloproliferative disorders.”
Credit: Walter and Eliza Hall
Institute of Medical Research
Investigators say they’ve determined how thrombopoietin (TPO) stimulates platelet production, and their findings may have implications for myeloproliferative neoplasms.
Researchers have long known that TPO is responsible for signaling cells in the bone marrow to produce platelets, but precisely which cells respond to TPO’s signals has been unclear.
Now, a group of investigators studying the TPO receptor Mpl have pinpointed those cells and made an unexpected discovery.
“Thrombopoietin did not directly stimulate the platelet’s ‘parent’ cells—the megakaryocytes—to make more platelets,” said study author Ashley Ng, PhD, of the Walter and Eliza Hall Institute of Medical Research in Victoria, Australia.
“Thrombopoietin signals actually acted on stem cells and progenitor cells, several generations back.”
Dr Ng and his colleagues reported these findings in PNAS.
The researchers had generated mice that express the Mpl receptor normally on stem and progenitor cells but lack expression on megakaryocytes and platelets. And these mice exhibited “profound” megakaryocytosis and thrombocytosis, as well as “remarkable” expansion of megakaryocyte-committed and multipotent progenitor cells.
“The progenitor and stem cells in the bone marrow began massively expanding and effectively turned the bone marrow into a megakaryocyte-making machine,” Dr Ng said.
Furthermore, although the progenitor cells showed signs of chronic TPO overstimulation, TPO levels were normal. This suggests that stem and progenitor cells expressing Mpl were responsible for TPO clearance, according to the investigators.
“Our findings support a theory whereby megakaryocytes and platelets control platelet numbers by ‘mopping up’ excess amounts of thrombopoietin in the bone marrow,” Dr Ng said. “In fact, we show this ‘mopping up’ action is absolutely essential in preventing blood disease where too many megakaryocytes and platelets are produced.”
So the researchers believe these findings will have implications for myeloproliferative neoplasms, particularly essential thrombocythemia.
“[P]revious studies have shown megakaryocytes and platelets in people with essential thrombocythemia have fewer Mpl receptors, which fits our model for excessive platelet production,” Dr Ng said.
To add support to their model, the investigators compared the progenitor cells responsible for overproducing megakaryocytes in their model to progenitor cells from patients with essential thrombocythemia. Both sets of cells showed a TPO stimulation signature.
“We think this study now provides a comprehensive model of how thrombopoietin controls platelet production,” Dr Ng said, “and perhaps gives some insight into the biology and mechanism behind specific myeloproliferative disorders.”