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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 Article has an altmetric score of 11

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

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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 1

Megakaryocytes transfer mitochondria to mesenchymal stem cells.

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Megakaryocytes transfer mitochondria to mesenchymal stem cells.
C57BL/6 ...
C57BL/6 murine MKs were cultured together with C57BL/6 MSCs or cultured alone. By flow cytometry, MKs from cocultures were analyzed for (A) mean fluorescence intensity (MFI) of mitotracker green (MTG) (n = 5) and (B) MFI of MTG from human cord blood CD34+ cell-derived MKs cocultured with human bone marrow MSCs (n = 4). (C) RT-PCR expression of Nd1/Hk2 in murine MKs from cocultures (n = 5). (D) C57BL/6 murine MKs were cultured together with MSCs from PhAM-floxed;E2a-cre mice or cultured alone. MFI of mitochondria PhAM signal in MKs by flow cytometry (n = 5). (E) Wild-type murine MSCs were cultured together with murine MKs from PhAM-floxed;E2a-cre mice or cultured alone. MFI of PhAM mitochondrial signal in MSCs by flow cytometry (n = 4). (F) Schematic of transplant design in which C57BL/6 mice were transplanted with PhAM-floxed;E2a-cre bone marrow cells or PhAM-floxed;E2a-cre mice were transplanted with C57BL/6 cells. (G) Bone marrow MSCs analyzed from transplanted mice for percentage PhAM+ MSCs and (H) numbers of PhAM+ MSCs per femur. (I) Bone marrow MKs analyzed from transplanted mice for percentage PhAM+ MKs and (J) numbers of PhAM+ MKs per femur. n = 3–4 mice for G–J. *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.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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