The secret life of a megakaryocyte: emerging roles in bone marrow homeostasis control

Abstract

SUMMARY Megakaryocytes are rare cells found in the bone marrow, responsible for the everyday production and release of millions of platelets into the bloodstream. Since the discovery and cloning, in 1994, of their principal humoral factor, thrombopoietin, and its receptor c-Mpl, many efforts have been directed to define the mechanisms underlying an efficient platelet production. However, more recently different studies have pointed out new roles for megakaryocytes as regulators of bone marrow homeostasis and physiology. In this review we discuss the interaction and the reciprocal regulation of megakaryocytes with the different cellular and extracellular components of the bone marrow environment. Finally, we provide evidence that these processes may concur to the reconstitution of the bone marrow environment after injury and their deregulation may lead to the development of a series of inherited or acquired pathologies.

JAK2V617F-mutant megakaryocytes contribute to hematopoietic stem/progenitor cell expansion in a model of murine myeloproliferation

“…MKs secrete a broad array of cytokines to regulate hematopoiesis. 46 To begin to understand the MK signals responsible for E-SLAM expansion in Pf4/FF1 mice, we measured the expression levels of FGF1 , Pf4 , Transforming growth factor beta 1 ( TGFb-1 ), Chemokine (C-X-C motif) ligand 12 ( CXCL12 ), VEGFa , chemokine (C-X-C motif) receptor 4 ( CXCR4 ) in Pf4/FF1 ( n = 4) and control MKs ( n = 3) using quantitative PCR (qPCR). We confirmed that there was upregulation of FGF1 (twofold, P = 0.004) in Pf4/FF1 MKs compared with control MKs (Figure 6c).…”

“…19–23,46,55,56 To investigate how JAK2 V617F -mutant MKs affect E-SLAM cell numbers and function, we performed a series of experiments. Although there was upregulation of FGF1, which positively expand MKs and facilitate HSPC expansion during stress hematopoiesis, in Pf4/FF1 MKs compared with control MKs, Pf4/FF1 MKCM suppressed E-SLAM cell proliferation in vitro , suggesting that the sum of the MK humoral influences is not responsible for the expansion of E-SLAM cells witnessed in our studies.…”

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

“…In particular, we showed that TPO is a pivotal regulator of this function by inducing TGF-β1 release, thus controlling ECM component synthesis in an autocrine manner. TGF-β1, as well as other soluble factors (e.g., ADP, VEGF, PF4) and ECM components (e.g., vWF, fibronectin), have been shown to be constitutively released by megakaryocytes to regulate their own differentiation and proplatelet formation [134,136,142,143,144,145,146], indicating that in physiological conditions megakaryocytes can activate an autocrine/paracrine loop which contribute to both their own development and overall bone marrow homeostasis [147]. Consistently, impaired synthesis and release of these proteins has been linked to altered megakaryocyte maturation, proplatelet formation and/or ECMs production [141,142,143,148], leading to a broad spectrum of clinical outcomes, from defective peripheral blood platelet count to deregulated bone marrow homeostasis [147,149,150].…”

Revealing eltrombopags promotion of human megakaryopoiesis through AKT/ERK-dependent pathway activation

“…1,2 The failure of HSCs to guarantee the physiologic homeostasis of one or more progenitors for circulating blood cells leads to pathologic conditions, such as aplastic anemia (AA) or myelodysplastic syndromes (MDS), characterized by peripheral pancytopenia of heterogeneous severity. 3,4 A selective cytopenia of blood platelets, namely thrombocytopenia, may occur because of mutations in genes relevant for the functions of maturing megakaryocytic progenitors, as in inherited thrombocytopenias (IT).…”