Megakaryocytes in pulmonary diseases

Abstract

Megakaryocytes (MKs) are typical cellular components in the circulating blood flowing from the heart into the lungs. Physiologically, MKs function as an important regulator of platelet production and immunoregulation. However, dysfunction in MKs is considered a trigger in various diseases. It has been described that the lung is an important site of platelet biogenesis from extramedullary MKs, which may play an essential role in various pulmonary diseases. With detailed studies, there are different degrees of numerical changes of MKs in coronavirus disease 2019 (COVID-19), acute respiratory distress syndrome (ARDS), chronic obstructive pulmonary disease (COPD), lung cancer, pulmonary fibrosis (PF), and other pulmonary diseases. Also, MKs inhibit or promote the development of pulmonary diseases through various pathways. Here, we summarize the current knowledge of MKs in pulmonary diseases, highlighting the physiological functions and integrated molecular mechanisms. We aim to shine new light on not only the subsequent study of MKs but also the diagnosis and treatment of pulmonary diseases.

Introduction

Megakaryocytes (MKs) are precursor cells in the blood system responsible for producing platelets (PLT) [1]. Like other blood cells, MKs are derived from hematopoietic stem cell, which found mainly in bone marrow, producing all blood cells in the circulatory system [1]. According to the classical hematopoietic model, HSC develops into megakaryocyte progenitor (MkP) through the gradual differentiation process of long-term HSC, short-term HSC, multipotent progenitors (MPP) and bipo-tent megakaryocyte-erythrocyte progenitor (MEP) [1]. Recent studies have shown that HSC contain a subset of cells with biased megakaryocyte potential, which can rapidly differentiate into MKs to effectively replenish PLT during inflammatory stress without going through MPP and MEP stages [2]. MkP maintains self-renewal through active mitosis. When confronted with some as-yet unidentified triggering event, MkP stops mitosis and enters a progress called endomitosis, in which the nucleus and cells grow in size, DNA continues to replicate but neither the nucleus nor the cytoplasm divides, and in this way, a single giant nucleus is formed with between 4 and 16 times the DNA of normal diploid DNA (hence the name MKs) [3]. This is also a classic example of developmentally regulated polyploidization in mammals. After completion of endomitosis, the cytoplasm of MKs begins to expand rapidly, filling with platelet-specific particles and forming an elaborate and highly convoluted invaginal membrane system (IMS) in preparation for platelet formation and release [4]. The main job of MKs is to produce and replenish platelets to maintain the body's normal coagulation function. Toxins, alcohol intake, and vitamin B12 deficiency can inhibit endomitosis and maturation of MKs. Some drugs, such as Bortezomib, can reduce PLT shedding in existing mature MKs, leading to thrombocytopenia and increasing the risk of bleeding [3]. Apoptosis of MKs caused by antiplatelet antibodies and cytotoxic T cells is the main cause of immune thrombocytopenia (ITP) [3]. In addition to acting as precursors to PLT, MKs can promote angiogenesis, bone formation [5], [6]and even maintain homeostatic quiescence [7], [8], [9] (important for stemness of HSC) by releasing mediators such as vascular endothelial growth factor and transforming growth factor (TGF). Both MKs and PLT are believed to have inflammatory cell functions and play an active role in innate and acquired immunity [10]. Notably, MKs can play a pro-inflammatory role independently of PLT, such as the transfer of IL-1-rich microparticles released by MKs to synovial tissues that aggravate inflammatory arthritis [10].

MKs were discovered in the lung early in 1893 [11]. Since then, much more information about indirect signs of platelet biogenesis in the lung has become available, which manifests that MKs decrease with PLT release after blood passes through the pulmonary circulation [12], [13], [14], [15]. The process by which MKs release PLT in the lung has not been discovered until 2017 when it was first dynamically and directly observed through intravital microscopy [16]. Based on those empirical studies, Lung has been recognized as one of the important biogenic sites of platelet in addition to bone marrow [16], [17]. Furthermore, MKs inherent in the lung have more essential physiological functions besides the same role of platelet biogenesis as those MKs in the bone marrow. More recent evidence suggests that pulmonary inherent MKs have various immunoregulatory functions [18], and transcriptome sequencing outcomes indicate that they express more mRNA related to innate immunity, such as Toll-like receptors (TLRs), chemokines, and cytokines [19].

It has aroused more and more attention that MKs are involved in the progression of pulmonary diseases, such as pneumonia, including coronavirus disease 2019 (COVID-19), acute respiratory distress syndrome (ARDS), chronic obstructive pulmonary disease (COPD), pulmonary fibrosis (PF), and lung cancer. The first thing that raises our concern is that pulmonary diseases are often accompanied by quantitative or functional abnormalities of MKs and PLT. In pneumonia caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), MKs not only involve in antiviral processes but also inhibit the advancement of COVID-19 by approaches like altering gene expression and participating in antigen presentation [20]. However, MKs can also play an adverse role against the diseases, like promoting the inflammatory response in ARDS and COPD [21], [22], [23]. In addition, MKs contain various fibrosis-related growth factors, which enables MKs to promote the development of fibrotic phenotype in PF through various pathways. More than that, MKs seem to have different roles in different stages of the disease. For instance, in lung cancer, MKs exert anti-tumor effects by inhibiting angiogenesis in the tumor microenvironment in the early stage, while exert tumor-promoting effects by releasing intracellular cytokines in the late stage. Notably, MKs play a crucial role in the development of pulmonary diseases. Targeting regulation of MKs holds promising prospects for the treatment of pulmonary diseases.

In this review, we first summarize the major physiological functions of MKs, especially the immunomodulatory effect. Then, we mainly focus on MKs' pathological function, including the molecular mechanisms in some comma pulmonary diseases. We also propose possible therapeutic ideas for those pulmonary diseases based on our current knowledge of MKs, hoping to shine new light on not only the subsequent study of MKs but also the diagnosis and treatment of pulmonary diseases.