Megakaryocytes transfer mitochondria to bone marrow mesenchymal stromal cells to lower platelet activation
Chengjie Gao, … , Karina Yazdanbakhsh, Avital Mendelson
Chengjie Gao, … , Karina Yazdanbakhsh, Avital Mendelson
Published February 27, 2025
Citation Information: J Clin Invest. 2025;135(8):e189801. https://doi.org/10.1172/JCI189801.
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Research Article Hematology

Megakaryocytes transfer mitochondria to bone marrow mesenchymal stromal cells to lower platelet activation

Abstract

Newly produced platelets acquire a low activation state, but whether the megakaryocyte plays a role in this outcome has not been fully uncovered. Mesenchymal stem cells (MSCs) were previously shown to promote platelet production and lower platelet activation. We found that healthy megakaryocytes transfer mitochondria to MSCs, which is mediated by connexin 43 (Cx43) gap junctions on MSCs and leads to platelets at a low energetic state with increased LYN activation, characteristic of resting platelets with increased LYN activation, characteristic of resting platelets. On the contrary, MSCs have a limited ability to transfer mitochondria to megakaryocytes. Sickle cell disease (SCD) is characterized by hemolytic anemia and results in heightened platelet activation, contributing to numerous disease complications. Platelets in SCD mice and human samples had a heightened energetic state with increased glycolysis. MSC exposure to heme in SCD led to decreased Cx43 expression and a reduced ability to uptake mitochondria from megakaryocytes. This prevented LYN activation in platelets and contributed to increased platelet activation at steady state. Altogether, our findings demonstrate an effect of hemolysis in the microenvironment leading to increased platelet activation in SCD. These findings have the potential to inspire new therapeutic targets to relieve thrombosis-related complications of SCD and other hemolytic conditions.

Authors

Chengjie Gao, Yitian Dai, Paul A. Spezza, Paul Boasiako, Alice Tang, Giselle Rasquinha, Hui Zhong, Bojing Shao, Yunfeng Liu, Patricia A. Shi, Cheryl A. Lobo, Xiuli An, Anqi Guo, William B. Mitchell, Deepa Manwani, Karina Yazdanbakhsh, Avital Mendelson

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Figure 6

Activation and metabolic profile of platelets from SCD mice.

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Activation and metabolic profile of platelets from SCD mice. Peripheral ...
Peripheral blood platelets from the Townes model of SCD or SA control mice were analyzed by flow cytometry for (A) CD62P expression (n = 3 mice) and (B) JonA expression (N = 4 mice). (C) Quantification of p-LYN expression by mean fluorescence intensity (MFI) (n = 6 mice). (D) Representative Seahorse glycolytic rate assay conducted on platelets from SCD mice compared with SA control mice (n = 3 mice). (E) Basal glycolysis levels (n = 3 mice). (F) Compensatory glycolysis levels (n = 3 mice). (G) Sorted MKs from SCD mice or SA control mice were analyzed by RT-PCR for glycolysis associated gene expression (n = 4 mice). Peripheral blood platelets from SCD or healthy donor patients were analyzed by (H) Seahorse glycolytic rate assay (n = 3). (I) Basal glycolysis levels of SCD platelets or healthy donor control platelets (n = 3). (J) Compensatory glycolysis of SCD platelets or healthy donor control platelets (n = 3). *P ≤ 0.05, **P ≤ 0.01, ***P ≤ 0.001, ****P ≤ 0.0001. Data were analyzed with 2-tailed, unpaired Student’s t test. Data are presented as mean ± SEM.