Thrombopoietin (TPO) is the chief cytokine that regulates megakaryocyte production, signaling through its receptor Mpl. The expression pattern of Mpl provides clues to the dual functions of TPO, with Mpl expressed predominantly on megakaryocytes, platelets, hemangioblasts and hematopoietic stem cells. TPO is chiefly responsible for megakaryocyte production but increasingly attention has turned to its role in maintaining hematopoietic stem cells. hematopoietic stem cells are required to initiate the production of all mature hematopoietic cells, but this differentiation needs to be balanced against self-renewal and quiescence to maintain the stem cell pool throughout life. TPO has been shown to support hematopoietic stem cell quiescence during adult hematopoiesis, with the loss of TPO signaling associated with bone marrow failure and thrombocytopenia.
With the availability of recombinant TPO and improved methods to purify haematopoietic stem and progenitor cell populations, further study indicated that the biological properties of TPO were not restricted to the megakaryocyte lineage. In vitro studies showed that TPO augmented survival and proliferation of CD34+ haematopoietic stem or progenitor cells, especially when used in combination with IL-3 or SCF. These data were further supported by the generation of transgenic mice lacking either Thpo or c-Mpl (Mpl). Transplantation of normal haematopoietic stem cell into Thpo/ mice resulted in a 15–20-fold decrease in stem cell expansion compared to transplantation into wild-type controls. additionally, c–Mpl/ ice exhibit a significant reduction n haematopoietic progenitors of all lineages and have only 10–20% of the normal number of haematopoietic stem cells. More recent work revealed an ntriguing paracrine role for TPO/c–Mpl in maintaining quiescent Tie2+ haematopoietic stem cells at the endosteal niche. They demonstrated that osteoblasts at the niche release TPO, supporting the quiescence of c-Mpl-expressing haematopoietic stem cells and inhibition of this interaction reduce the number of haematopoietic stem cells at the niche. We now know that TPO also plays a role in haematopoietic stem cell maintenance in humans, as congenital forms of amegakaryocytic thrombocytopenia often develop as a result of c-MPL (MPL) mutations, with the majority of such children developing aplastic anaemia in the first 1–5 years of life due to a diminishing pool of haematopoietic stem cells.
Haematopoietic stem cells transplantation is an important therapeutic procedure, but its application is often restricted by difficulties in ex vivo expansion and maintenance of haematopoietic stem cells. Similar to its ability to expand haematopoietic stem cells after transplantation, TPO can augment ex vivo expansion of haematopoietic stem cells to increase the pool available for transplantation, but it is far more effective when used in combination with other cytokines. Most cytokine combinations proposed include stem cell factor (SCF), fms-like tyrosine kinase 3 ligand (FL) and TPO. A nonpeptidyl small molecle agonist of MPL, NR-101, was found to be more efficient than TPO in expanding haematopoietic stem cells. Interestingly, this effect seemed to be specific to haematopoietic stem cells, as it was not more efficient than TPO in inducing megakaryocyte expansion.
• de Graaf C A, et al. Thrombopoietin and hematopoietic stem cells[J]. Cell cycle, 2011, 10(10): 1582-1589.
• Hitchcock I S, et al. Thrombopoietin from beginning to end[J]. British journal of haematology, 2014, 165(2): 259-268.