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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 3

MSC CX43 gap junctions mediate mitochondrial transfer from megakaryocytes.

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MSC CX43 gap junctions mediate mitochondrial transfer from megakaryocyte...
PhAM-floxed;E2a-cre murine MKs cultured together with C57BL/6 MSCs or MSCs from CX43-floxed;Lepr-cre mice. Following coculture, flow cytometry assessment of (A) mean fluorescence intensity (MFI) of PhAM signal in MKs (n = 5), (B) MFI of PhAM signal in platelets (n = 5), (C) MFI of PhAM signal in MSCs (n = 5), (D) CD62P expression on platelets (n = 4), and (E) JonA (αIIbβ3) expression on platelets (n = 4). (F) Representative Seahorse glycolytic rate assay conducted on MKs following coculture with wild-type or Gap19-treated MSCs (n = 3). (G) Basal glycolysis levels of MKs from coculture (n = 3). (H) Compensatory glycolysis of MKs following coculture (n = 3). (I) RT-PCR analysis of glycolytic genes (Pkm2, Pfkm, Hk1, and Slc3a3) in MKs from cocultures with either C57BL/6 MSCs or C57BL/6 MSCs pretreated with Gap19 to inhibit CX43 expression (n = 3–4). *P ≤ 0.05, **P ≤ 0.01. 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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