Pathophysiological Significance of Store-Operated Calcium Entry in Megakaryocyte Function: Opening New Paths for Understanding the Role of Calcium in Thrombopoiesis

Abstract

Store-Operated Calcium Entry (SOCE) is a universal calcium (Ca²⁺) influx mechanism expressed by several different cell types. It is now known that Stromal Interaction Molecule (STIM), the Ca²⁺ sensor of the intracellular compartments, together with Orai and Transient Receptor Potential Canonical (TRPC), the subunits of Ca²⁺ permeable channels on the plasma membrane, cooperate in regulating multiple cellular functions as diverse as proliferation, differentiation, migration, gene expression, and many others, depending on the cell type. In particular, a growing body of evidences suggests that a tight control of SOCE expression and function is achieved by megakaryocytes along their route from hematopoietic stem cells to platelet production. This review attempts to provide an overview about the SOCE dynamics in megakaryocyte development, with a focus on most recent findings related to its involvement in physiological and pathological thrombopoiesis.

Keywords: SOCE; calcium; calreticulin; megakaryocyte; myelofibrosis; platelet production.

Figure 1

Store-Operated Ca²⁺ Entry (SOCE) in physiological and pathological thrombopoiesis. (A) Bone marrow, contained in spongy bones, is a tridimensional network of branching sinusoids surrounding islets of hematopoietic cells. Within this environment hematopoietic stem cells (HSCs) undergo self-renewal as well as differentiation into committed lineages in order to support the physiological homeostasis of all blood cells. Megakaryopoiesis takes place under thrombopoietin stimulation, which promotes HSC commitment and differentiation toward megakaryocytes (MKs). In MKs with replete endoplasmic reticulum (ER), Stromal Interaction Molecule (STIM) is localized in an inactive configuration in the ER membrane. Depletion of Ca²⁺ stores triggers Ca²⁺ release from the ER through inositol-trisphosphate receptors (IP3R) and consequent Ca²⁺ dissociation form STIM, which oligomerize and translocate next to the plasma membrane. Then, STIM binding to Orai and Transient Receptor Potential Canonical (TRPC) results in opening of these channels and extracellular Ca²⁺ entry. The increased cytosolic Ca²⁺ concentration ([Ca²⁺]_i) in turn regulates cell proliferation, differentiation, migration and final platelet production; (B) An abnormal increase in [Ca²⁺]_i due to altered control of SOCE dynamics may result in pathological phenotypes such as higher proliferation and platelet production. Red arrow, increased with respect to physiological conditions.