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ResearchIn-Press PreviewHematology Open Access | 10.1172/JCI189801

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

Chengjie Gao,1 Yitian Dai,2 Paul A. Spezza,2 Paul Boasiako,2 Alice Tang,2 Giselle Rasquinha,2 Hui zhong,3 Bojing Shao,4 Yunfeng Liu,5 Patricia A. Shi,5 Cheryl A. Lobo,6 Xiuli An,7 Anqi Guo,5 William B. Mitchell,8 Deepa Manwani,9 Karina Yazdanbakhsh,5 and Avital Mendelson2

1Laboratory of Membrane Biology, New York Blood Center, New York, United States of America

2Laboratory of Stem Cell Biology and Engineering Research, New York Blood Center, New York, United States of America

3Laboratory of Immune Regulation, New York Blood Center, New York, United States of America

4Laboratory of Vascular Inflammation and Thrombosis Research, New York Blood Center, New York, United States of America

5Laboratory of Complement Biology, New York Blood Center, New York, United States of America

6Laboratory of Blood-Borne Parasites, New York Blood Center, New York, United States of America

7Membrane Disorders, New York Blood Center, New York, United States of America

8Department of Pediatrics, Montefiore Health Center, Albert Einstein College of Medicine, Bronx, United States of America

9Division of Pediatric Hematology-Oncology, Children's Hospital at Montefiore, Bronx, United States of America

Find articles by Gao, C. in: JCI | PubMed | Google Scholar

1Laboratory of Membrane Biology, New York Blood Center, New York, United States of America

2Laboratory of Stem Cell Biology and Engineering Research, New York Blood Center, New York, United States of America

3Laboratory of Immune Regulation, New York Blood Center, New York, United States of America

4Laboratory of Vascular Inflammation and Thrombosis Research, New York Blood Center, New York, United States of America

5Laboratory of Complement Biology, New York Blood Center, New York, United States of America

6Laboratory of Blood-Borne Parasites, New York Blood Center, New York, United States of America

7Membrane Disorders, New York Blood Center, New York, United States of America

8Department of Pediatrics, Montefiore Health Center, Albert Einstein College of Medicine, Bronx, United States of America

9Division of Pediatric Hematology-Oncology, Children's Hospital at Montefiore, Bronx, United States of America

Find articles by Dai, Y. in: JCI | PubMed | Google Scholar

1Laboratory of Membrane Biology, New York Blood Center, New York, United States of America

2Laboratory of Stem Cell Biology and Engineering Research, New York Blood Center, New York, United States of America

3Laboratory of Immune Regulation, New York Blood Center, New York, United States of America

4Laboratory of Vascular Inflammation and Thrombosis Research, New York Blood Center, New York, United States of America

5Laboratory of Complement Biology, New York Blood Center, New York, United States of America

6Laboratory of Blood-Borne Parasites, New York Blood Center, New York, United States of America

7Membrane Disorders, New York Blood Center, New York, United States of America

8Department of Pediatrics, Montefiore Health Center, Albert Einstein College of Medicine, Bronx, United States of America

9Division of Pediatric Hematology-Oncology, Children's Hospital at Montefiore, Bronx, United States of America

Find articles by Spezza, P. in: JCI | PubMed | Google Scholar

1Laboratory of Membrane Biology, New York Blood Center, New York, United States of America

2Laboratory of Stem Cell Biology and Engineering Research, New York Blood Center, New York, United States of America

3Laboratory of Immune Regulation, New York Blood Center, New York, United States of America

4Laboratory of Vascular Inflammation and Thrombosis Research, New York Blood Center, New York, United States of America

5Laboratory of Complement Biology, New York Blood Center, New York, United States of America

6Laboratory of Blood-Borne Parasites, New York Blood Center, New York, United States of America

7Membrane Disorders, New York Blood Center, New York, United States of America

8Department of Pediatrics, Montefiore Health Center, Albert Einstein College of Medicine, Bronx, United States of America

9Division of Pediatric Hematology-Oncology, Children's Hospital at Montefiore, Bronx, United States of America

Find articles by Boasiako, P. in: JCI | PubMed | Google Scholar

1Laboratory of Membrane Biology, New York Blood Center, New York, United States of America

2Laboratory of Stem Cell Biology and Engineering Research, New York Blood Center, New York, United States of America

3Laboratory of Immune Regulation, New York Blood Center, New York, United States of America

4Laboratory of Vascular Inflammation and Thrombosis Research, New York Blood Center, New York, United States of America

5Laboratory of Complement Biology, New York Blood Center, New York, United States of America

6Laboratory of Blood-Borne Parasites, New York Blood Center, New York, United States of America

7Membrane Disorders, New York Blood Center, New York, United States of America

8Department of Pediatrics, Montefiore Health Center, Albert Einstein College of Medicine, Bronx, United States of America

9Division of Pediatric Hematology-Oncology, Children's Hospital at Montefiore, Bronx, United States of America

Find articles by Tang, A. in: JCI | PubMed | Google Scholar

1Laboratory of Membrane Biology, New York Blood Center, New York, United States of America

2Laboratory of Stem Cell Biology and Engineering Research, New York Blood Center, New York, United States of America

3Laboratory of Immune Regulation, New York Blood Center, New York, United States of America

4Laboratory of Vascular Inflammation and Thrombosis Research, New York Blood Center, New York, United States of America

5Laboratory of Complement Biology, New York Blood Center, New York, United States of America

6Laboratory of Blood-Borne Parasites, New York Blood Center, New York, United States of America

7Membrane Disorders, New York Blood Center, New York, United States of America

8Department of Pediatrics, Montefiore Health Center, Albert Einstein College of Medicine, Bronx, United States of America

9Division of Pediatric Hematology-Oncology, Children's Hospital at Montefiore, Bronx, United States of America

Find articles by Rasquinha, G. in: JCI | PubMed | Google Scholar

1Laboratory of Membrane Biology, New York Blood Center, New York, United States of America

2Laboratory of Stem Cell Biology and Engineering Research, New York Blood Center, New York, United States of America

3Laboratory of Immune Regulation, New York Blood Center, New York, United States of America

4Laboratory of Vascular Inflammation and Thrombosis Research, New York Blood Center, New York, United States of America

5Laboratory of Complement Biology, New York Blood Center, New York, United States of America

6Laboratory of Blood-Borne Parasites, New York Blood Center, New York, United States of America

7Membrane Disorders, New York Blood Center, New York, United States of America

8Department of Pediatrics, Montefiore Health Center, Albert Einstein College of Medicine, Bronx, United States of America

9Division of Pediatric Hematology-Oncology, Children's Hospital at Montefiore, Bronx, United States of America

Find articles by zhong, H. in: JCI | PubMed | Google Scholar

1Laboratory of Membrane Biology, New York Blood Center, New York, United States of America

2Laboratory of Stem Cell Biology and Engineering Research, New York Blood Center, New York, United States of America

3Laboratory of Immune Regulation, New York Blood Center, New York, United States of America

4Laboratory of Vascular Inflammation and Thrombosis Research, New York Blood Center, New York, United States of America

5Laboratory of Complement Biology, New York Blood Center, New York, United States of America

6Laboratory of Blood-Borne Parasites, New York Blood Center, New York, United States of America

7Membrane Disorders, New York Blood Center, New York, United States of America

8Department of Pediatrics, Montefiore Health Center, Albert Einstein College of Medicine, Bronx, United States of America

9Division of Pediatric Hematology-Oncology, Children's Hospital at Montefiore, Bronx, United States of America

Find articles by Shao, B. in: JCI | PubMed | Google Scholar

1Laboratory of Membrane Biology, New York Blood Center, New York, United States of America

2Laboratory of Stem Cell Biology and Engineering Research, New York Blood Center, New York, United States of America

3Laboratory of Immune Regulation, New York Blood Center, New York, United States of America

4Laboratory of Vascular Inflammation and Thrombosis Research, New York Blood Center, New York, United States of America

5Laboratory of Complement Biology, New York Blood Center, New York, United States of America

6Laboratory of Blood-Borne Parasites, New York Blood Center, New York, United States of America

7Membrane Disorders, New York Blood Center, New York, United States of America

8Department of Pediatrics, Montefiore Health Center, Albert Einstein College of Medicine, Bronx, United States of America

9Division of Pediatric Hematology-Oncology, Children's Hospital at Montefiore, Bronx, United States of America

Find articles by Liu, Y. in: JCI | PubMed | Google Scholar |

1Laboratory of Membrane Biology, New York Blood Center, New York, United States of America

2Laboratory of Stem Cell Biology and Engineering Research, New York Blood Center, New York, United States of America

3Laboratory of Immune Regulation, New York Blood Center, New York, United States of America

4Laboratory of Vascular Inflammation and Thrombosis Research, New York Blood Center, New York, United States of America

5Laboratory of Complement Biology, New York Blood Center, New York, United States of America

6Laboratory of Blood-Borne Parasites, New York Blood Center, New York, United States of America

7Membrane Disorders, New York Blood Center, New York, United States of America

8Department of Pediatrics, Montefiore Health Center, Albert Einstein College of Medicine, Bronx, United States of America

9Division of Pediatric Hematology-Oncology, Children's Hospital at Montefiore, Bronx, United States of America

Find articles by Shi, P. in: JCI | PubMed | Google Scholar |

1Laboratory of Membrane Biology, New York Blood Center, New York, United States of America

2Laboratory of Stem Cell Biology and Engineering Research, New York Blood Center, New York, United States of America

3Laboratory of Immune Regulation, New York Blood Center, New York, United States of America

4Laboratory of Vascular Inflammation and Thrombosis Research, New York Blood Center, New York, United States of America

5Laboratory of Complement Biology, New York Blood Center, New York, United States of America

6Laboratory of Blood-Borne Parasites, New York Blood Center, New York, United States of America

7Membrane Disorders, New York Blood Center, New York, United States of America

8Department of Pediatrics, Montefiore Health Center, Albert Einstein College of Medicine, Bronx, United States of America

9Division of Pediatric Hematology-Oncology, Children's Hospital at Montefiore, Bronx, United States of America

Find articles by Lobo, C. in: JCI | PubMed | Google Scholar

1Laboratory of Membrane Biology, New York Blood Center, New York, United States of America

2Laboratory of Stem Cell Biology and Engineering Research, New York Blood Center, New York, United States of America

3Laboratory of Immune Regulation, New York Blood Center, New York, United States of America

4Laboratory of Vascular Inflammation and Thrombosis Research, New York Blood Center, New York, United States of America

5Laboratory of Complement Biology, New York Blood Center, New York, United States of America

6Laboratory of Blood-Borne Parasites, New York Blood Center, New York, United States of America

7Membrane Disorders, New York Blood Center, New York, United States of America

8Department of Pediatrics, Montefiore Health Center, Albert Einstein College of Medicine, Bronx, United States of America

9Division of Pediatric Hematology-Oncology, Children's Hospital at Montefiore, Bronx, United States of America

Find articles by An, X. in: JCI | PubMed | Google Scholar

1Laboratory of Membrane Biology, New York Blood Center, New York, United States of America

2Laboratory of Stem Cell Biology and Engineering Research, New York Blood Center, New York, United States of America

3Laboratory of Immune Regulation, New York Blood Center, New York, United States of America

4Laboratory of Vascular Inflammation and Thrombosis Research, New York Blood Center, New York, United States of America

5Laboratory of Complement Biology, New York Blood Center, New York, United States of America

6Laboratory of Blood-Borne Parasites, New York Blood Center, New York, United States of America

7Membrane Disorders, New York Blood Center, New York, United States of America

8Department of Pediatrics, Montefiore Health Center, Albert Einstein College of Medicine, Bronx, United States of America

9Division of Pediatric Hematology-Oncology, Children's Hospital at Montefiore, Bronx, United States of America

Find articles by Guo, A. in: JCI | PubMed | Google Scholar

1Laboratory of Membrane Biology, New York Blood Center, New York, United States of America

2Laboratory of Stem Cell Biology and Engineering Research, New York Blood Center, New York, United States of America

3Laboratory of Immune Regulation, New York Blood Center, New York, United States of America

4Laboratory of Vascular Inflammation and Thrombosis Research, New York Blood Center, New York, United States of America

5Laboratory of Complement Biology, New York Blood Center, New York, United States of America

6Laboratory of Blood-Borne Parasites, New York Blood Center, New York, United States of America

7Membrane Disorders, New York Blood Center, New York, United States of America

8Department of Pediatrics, Montefiore Health Center, Albert Einstein College of Medicine, Bronx, United States of America

9Division of Pediatric Hematology-Oncology, Children's Hospital at Montefiore, Bronx, United States of America

Find articles by Mitchell, W. in: JCI | PubMed | Google Scholar

1Laboratory of Membrane Biology, New York Blood Center, New York, United States of America

2Laboratory of Stem Cell Biology and Engineering Research, New York Blood Center, New York, United States of America

3Laboratory of Immune Regulation, New York Blood Center, New York, United States of America

4Laboratory of Vascular Inflammation and Thrombosis Research, New York Blood Center, New York, United States of America

5Laboratory of Complement Biology, New York Blood Center, New York, United States of America

6Laboratory of Blood-Borne Parasites, New York Blood Center, New York, United States of America

7Membrane Disorders, New York Blood Center, New York, United States of America

8Department of Pediatrics, Montefiore Health Center, Albert Einstein College of Medicine, Bronx, United States of America

9Division of Pediatric Hematology-Oncology, Children's Hospital at Montefiore, Bronx, United States of America

Find articles by Manwani, D. in: JCI | PubMed | Google Scholar

1Laboratory of Membrane Biology, New York Blood Center, New York, United States of America

2Laboratory of Stem Cell Biology and Engineering Research, New York Blood Center, New York, United States of America

3Laboratory of Immune Regulation, New York Blood Center, New York, United States of America

4Laboratory of Vascular Inflammation and Thrombosis Research, New York Blood Center, New York, United States of America

5Laboratory of Complement Biology, New York Blood Center, New York, United States of America

6Laboratory of Blood-Borne Parasites, New York Blood Center, New York, United States of America

7Membrane Disorders, New York Blood Center, New York, United States of America

8Department of Pediatrics, Montefiore Health Center, Albert Einstein College of Medicine, Bronx, United States of America

9Division of Pediatric Hematology-Oncology, Children's Hospital at Montefiore, Bronx, United States of America

Find articles by Yazdanbakhsh, K. in: JCI | PubMed | Google Scholar

1Laboratory of Membrane Biology, New York Blood Center, New York, United States of America

2Laboratory of Stem Cell Biology and Engineering Research, New York Blood Center, New York, United States of America

3Laboratory of Immune Regulation, New York Blood Center, New York, United States of America

4Laboratory of Vascular Inflammation and Thrombosis Research, New York Blood Center, New York, United States of America

5Laboratory of Complement Biology, New York Blood Center, New York, United States of America

6Laboratory of Blood-Borne Parasites, New York Blood Center, New York, United States of America

7Membrane Disorders, New York Blood Center, New York, United States of America

8Department of Pediatrics, Montefiore Health Center, Albert Einstein College of Medicine, Bronx, United States of America

9Division of Pediatric Hematology-Oncology, Children's Hospital at Montefiore, Bronx, United States of America

Find articles by Mendelson, A. in: JCI | PubMed | Google Scholar

Published February 27, 2025 - More info

J Clin Invest. https://doi.org/10.1172/JCI189801.
Copyright © 2025, Gao et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published February 27, 2025 - Version history
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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 healthy megakaryocytes transfer mitochondria to MSCs mediated by Connexin 43 (Cx43) gap junctions on MSCs, which leads to platelets at a low energetic state 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 patient 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.

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  • Version 1 (February 27, 2025): In-Press Preview
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