During the clinical course of coronavirus disease 2019 (COVID‐19), it has been observed that hepatic injury occurs in a significant proportion of patients, particularly in those with severe or critical illness. Mild increase in sinusoidal lymphocytic infiltration, sinusoidal dilatation, steatosis and multifocal hepatic necrosis are the pathologic changes reported. Direct viral‐induced cellular injuries and potential hepatotoxicity from therapeutic drugs are two likely underlying mechanisms. In addition, the pre‐existing chronic liver disease exacerbated during COVID‐19, and COVID‐19‐related hyperinflammatory reactions may contribute to liver injury as well. Further studies of additional autopsy cases will help clarifying these possibilities.

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Megakaryocytes (MKs), the platelet progenitor cell, play important roles in hematopoietic stem cell (HSC) maintenance and immunity. However, it is not known whether these diverse programs are executed by a single population or by distinct subsets of cells. Here, we manually-isolated primary CD41+ MKs from the bone marrow (BM) of mice and human donors based on ploidy (2N-32N), performed single-cell RNA sequencing analysis. We found that cellular heterogeneity existed within three distinct subpopulations possessing gene signatures related to platelet-generation, HSC niche interaction, and inflammatory responses, respectively. In situ immunostaining of mouse BM demonstrated that platelet-generation and HSC-niche related MKs were physically in close proximity to blood vessels and HSCs, respectively. Proplatelets, which could give rise to platelets under the blood shear forces, were predominantly formed on platelet-generation subset. Remarkably, the inflammatory responses subpopulation, consisting generally of low-ploidy LSP1+ and CD53+ MKs (≤8N), represented approximately 5% of total MKs in the BM. These MKs could specifically respond to pathogen infections in mice. Rapid expansion of this population was accompanied by strong upregulation of a pre-existing PU.1 and IRF-8-associated monocytic-like transcriptional program involved in pathogen recognition and clearance, as well as antigen presentation. Consistently, isolated primary CD53+ cells were capable to engulf and digest bacteria and to stimulate T cells in vitro. Together, our findings uncover new molecular, spatial, and functional heterogeneity within MKs in vivo and demonstrate the existence of a specialized MK subpopulation that may act as a new type of immune cell.