Kellie Machlus, Ph.D.
Hematopoiesis is the stepwise process by which hematopoietic stem cells (HSCs) undergo differentiation to produce all the mature blood lineages. In 1995, TPO and its receptor c-Mpl were found to be the key drivers of megakaryocyte (MK) differentiation from their HSC progenitors. However, mice lacking either c-Mpl or TPO successfully produce both MKs and platelets, indicating a role for other regulators. Nevertheless, limited substrates that regulate thrombopoiesis in vitro or in vivo have been identified, and there has yet to be a study to successfully delineate a non-TPO related protein and corresponding signaling pathway that effectively inhibits or initiates MK differentiation and maturation. One of the main goals of my lab is to find TPO-independent mediators of MK differentiation and maturation. These novel therapeutic targets have the potential to precisely and efficiently regulate MK number and ultimately platelet production in patients.
Modulation of Megakaryocyte Differentiation and Maturation During Inflammation
In the setting of physiological stress, platelet counts can rise, resulting in thrombocytosis. What initiates this up-regulation is not well understood and has largely been attributed to an inflammatory response and increased cytokine release. One cytokine that is highly expressed in inflammatory states is CCL5 (RANTES). Our studies have revealed that CCL5 administration results in MKs that are more mature (higher ploidy) and that this increase in MK maturation may be caused by inhibition of the pro-apoptotic protein BAD. Apoptosis inhibition may allow MKs to continue maturation and move forward to the final stages of platelet production. In times of inflammation, CCL5 signaling through CCR5 may work to 1) increase the number of hematopoietic stem cells that differentiate into MKs and/or 2) augment MK maturation through enhanced prosurvival signaling. The mechanisms of how CCL5 contributes to thrombocytosis is an ongoing project in the lab.
Megakaryocytes in the process of making proplatelets.
Schematic of megakaryocyte maturation (Machlus et al., JCB, 2013).
Molecular Mechanisms of Platelet Production
Circulating blood platelets are specialized cells that function to prevent bleeding and minimize blood vessel injury. As such, platelets play a critical role in both normal and disease physiology. The currently favored model of platelet formation states that MKs release platelets by extending long, branching processes, proplatelets, into sinusoidal blood vessels. Despite the importance of platelets in thrombosis and hemostasis, the cellular and molecular basis by which MKs complete differentiation and release platelets is poorly understood. In particular, little is known about what triggers resting, mature MKs to begin forming and releasing proplatelets. The goal of this project is to identify molecules and pathways that power platelet production. These novel therapeutic targets have the potential to accelerate platelet production in patients with thrombocytopenia.