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Updated: Jun 12, 2025
Megakaryocyte Differentiation and Platelet Formation from Human Cord Blood-derived CD34+ Cells
Published on: December 27, 2017
Long-lived lung megakaryocytes contribute to platelet recovery in thrombocytopenia models
Alison C Livada1,2, Kathleen E McGrath3, Michael W Malloy1
1Aab Cardiovascular Research Institute.
Abstract:
Lung megakaryocytes (Mks) are largely extravascular with an immune phenotype (1). Because bone marrow (BM) Mks are short lived, it has been assumed that extravascular lung Mks are constantly "seeded" from the BM. To investigate lung Mk origins and how origin affects their functions, we developed methods to specifically label lung Mks using CFSE dye and biotin delivered via the oropharyngeal route. Labeled lung Mks were present for up to 4 months, while BM Mks had a lifespan of less than 1 week. In a parabiosis model, lung Mks were partially replaced over 1 month from a circulating source. Unlike tissue-resident macrophages, using MDS1-Cre-ERT2 TdTomato mice, we found that lung Mks arose from hematopoietic stem cells. However, studies with FlkSwitch mTmG mice showed that lung Mks were derived from a Flt3-independent lineage that did not go through a multipotent progenitor. CFSE labeling to track lung Mk-derived platelets showed that approximately 10% of circulating platelets were derived from lung-resident Mks at steady state, but in sterile thrombocytopenia this was doubled (~20%). Lung-derived platelets were similarly increased in a malaria infection model (Plasmodium yoelii) typified by thrombocytopenia. These studies indicate that lung Mks arise from a Flt3- BM source, are long-lived, and contribute more platelets during thrombocytopenia.
Insights
Lung megakaryocytes (Mks) are long-lived and originate from a specific bone marrow (BM) source. These lung Mks contribute significantly to platelet production, especially during thrombocytopenia.
Area of Science:
- Hematology
- Immunology
- Cell Biology
Background:
- Lung megakaryocytes (Mks) are primarily extravascular and possess immune characteristics.
- The short lifespan of bone marrow (BM) Mks led to the assumption that lung Mks are continuously supplied by the BM.
Purpose of the Study:
- To investigate the origin and functional implications of lung Mks.
- To differentiate lung Mk lifespan and contribution to platelet production compared to BM Mks.
Main Methods:
- Utilized oropharyngeal delivery of CFSE dye and biotin for specific lung Mk labeling.
- Employed parabiosis models and genetic lineage tracing (MDS1-Cre-ERT2 TdTomato, FlkSwitch mTmG mice) to track Mk origins.
- Assessed platelet production from lung Mks in steady state, sterile thrombocytopenia, and a malaria infection model (Plasmodium yoelii).
Main Results:
- Labeled lung Mks persisted for up to 4 months, contrasting with BM Mks' lifespan (<1 week).
- Lung Mks originate from hematopoietic stem cells via a Flt3-independent lineage, not through multipotent progenitors.
- Lung-resident Mks contribute ~10% of circulating platelets at steady state, increasing to ~20% during thrombocytopenia and malaria infection.
Conclusions:
- Lung Mks are long-lived, self-sustaining cells originating from a Flt3- independent BM source.
- Lung Mks play a crucial role in platelet production, particularly under conditions of thrombocytopenia.
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