PMID- 37501059
OWN - NLM
STAT- MEDLINE
DCOM- 20230731
LR  - 20230802
IS  - 1756-8722 (Electronic)
IS  - 1756-8722 (Linking)
VI  - 16
IP  - 1
DP  - 2023 Jul 27
TI  - Hyperhomocysteinemia potentiates megakaryocyte differentiation and thrombopoiesis 
      via GH-PI3K-Akt axis.
PG  - 84
LID - 10.1186/s13045-023-01481-x [doi]
LID - 84
AB  - Hyperhomocysteinemia (HHcy) is closely associated with thrombotic diseases such 
      as myocardial infarction and stroke. Enhanced platelet activation was observed in 
      animals and humans with HHcy. However, the influence of HHcy on thrombopoiesis 
      remains largely unknown. Here, we reported increased platelet count (PLT) in mice 
      and zebrafish with HHcy. In hypertensive patients (n = 11,189), higher serum 
      level of total Hcy was observed in participants with PLT >/= 291 x 10(9)/L (full 
      adjusted beta, 0.59; 95% CI 0.14, 1.04). We used single-cell RNA sequencing 
      (scRNA-seq) to characterize the impact of Hcy on transcriptome, cellular 
      heterogeneity, and developmental trajectories of megakaryopoiesis from human 
      umbilical cord blood (hUCB) CD34(+) cells. Together with in vitro and in vivo 
      analysis, we demonstrated that Hcy promoted megakaryocytes (MKs) differentiation 
      via growth hormone (GH)-PI3K-Akt axis. Moreover, the effect of Hcy on 
      thrombopoiesis is independent of thrombopoietin (TPO) because administration of 
      Hcy also led to a significant increase of PLT in homozygous TPO receptor (Mpl) 
      mutant mice and zebrafish. Administration of melatonin effectively reversed 
      Hcy-induced thrombopoiesis in mice. ScRNA-seq showed that melatonin abolished 
      Hcy-facilitated MK differentiation and maturation, inhibited the activation of 
      GH-PI3K-Akt signaling. Our work reveals a previously unrecognized role of HHcy in 
      thrombopoiesis and provides new insight into the mechanisms by which HHcy confers 
      an increased thrombotic risk.Trial Registration clinicaltrials.gov Identifier: 
      NCT00794885.
CI  - (c) 2023. The Author(s).
FAU - Lei, Wenjing
AU  - Lei W
AD  - The State Key Laboratory of Organ Failure Research, National Clinical Research 
      Center of Kidney Disease, Key Laboratory of Organ Failure Research (Ministry of 
      Education), Division of Nephrology, Nanfang Hospital, Southern Medical 
      University, North Guangshou Avenue 1838, Guangzhou, 510515, Guangdong, People's 
      Republic of China.
AD  - Division of Nephrology, The First Affiliated Hospital of USTC, Division of Life 
      Sciences and Medicine, University of Science and Technology of China, Hefei, 
      230001, Anhui, People's Republic of China.
FAU - Liu, Zhuoliang
AU  - Liu Z
AD  - The State Key Laboratory of Organ Failure Research, National Clinical Research 
      Center of Kidney Disease, Key Laboratory of Organ Failure Research (Ministry of 
      Education), Division of Nephrology, Nanfang Hospital, Southern Medical 
      University, North Guangshou Avenue 1838, Guangzhou, 510515, Guangdong, People's 
      Republic of China.
FAU - Su, Zhiyuan
AU  - Su Z
AD  - The State Key Laboratory of Organ Failure Research, National Clinical Research 
      Center of Kidney Disease, Key Laboratory of Organ Failure Research (Ministry of 
      Education), Division of Nephrology, Nanfang Hospital, Southern Medical 
      University, North Guangshou Avenue 1838, Guangzhou, 510515, Guangdong, People's 
      Republic of China.
FAU - Meng, Panpan
AU  - Meng P
AD  - Division of Cell, Developmental and Integrative Biology, School of Medicine, 
      South China University of Technology, Guangzhou, 510006, Guangdong, People's 
      Republic of China.
FAU - Zhou, Chun
AU  - Zhou C
AD  - The State Key Laboratory of Organ Failure Research, National Clinical Research 
      Center of Kidney Disease, Key Laboratory of Organ Failure Research (Ministry of 
      Education), Division of Nephrology, Nanfang Hospital, Southern Medical 
      University, North Guangshou Avenue 1838, Guangzhou, 510515, Guangdong, People's 
      Republic of China.
FAU - Chen, Xiaomei
AU  - Chen X
AD  - The State Key Laboratory of Organ Failure Research, National Clinical Research 
      Center of Kidney Disease, Key Laboratory of Organ Failure Research (Ministry of 
      Education), Division of Nephrology, Nanfang Hospital, Southern Medical 
      University, North Guangshou Avenue 1838, Guangzhou, 510515, Guangdong, People's 
      Republic of China.
FAU - Hu, Zheng
AU  - Hu Z
AD  - The State Key Laboratory of Organ Failure Research, National Clinical Research 
      Center of Kidney Disease, Key Laboratory of Organ Failure Research (Ministry of 
      Education), Division of Nephrology, Nanfang Hospital, Southern Medical 
      University, North Guangshou Avenue 1838, Guangzhou, 510515, Guangdong, People's 
      Republic of China.
FAU - Xiao, An
AU  - Xiao A
AD  - The State Key Laboratory of Organ Failure Research, National Clinical Research 
      Center of Kidney Disease, Key Laboratory of Organ Failure Research (Ministry of 
      Education), Division of Nephrology, Nanfang Hospital, Southern Medical 
      University, North Guangshou Avenue 1838, Guangzhou, 510515, Guangdong, People's 
      Republic of China.
FAU - Zhou, Miaomiao
AU  - Zhou M
AD  - The State Key Laboratory of Organ Failure Research, National Clinical Research 
      Center of Kidney Disease, Key Laboratory of Organ Failure Research (Ministry of 
      Education), Division of Nephrology, Nanfang Hospital, Southern Medical 
      University, North Guangshou Avenue 1838, Guangzhou, 510515, Guangdong, People's 
      Republic of China.
FAU - Huang, Liping
AU  - Huang L
AD  - Department of Obstetrics and Gynecology, Nanfang Hospital, Southern Medical 
      University, Guangzhou, 510515, Guangdong, People's Republic of China.
FAU - Zhang, Yiyue
AU  - Zhang Y
AD  - Division of Cell, Developmental and Integrative Biology, School of Medicine, 
      South China University of Technology, Guangzhou, 510006, Guangdong, People's 
      Republic of China.
FAU - Qin, Xianhui
AU  - Qin X
AD  - The State Key Laboratory of Organ Failure Research, National Clinical Research 
      Center of Kidney Disease, Key Laboratory of Organ Failure Research (Ministry of 
      Education), Division of Nephrology, Nanfang Hospital, Southern Medical 
      University, North Guangshou Avenue 1838, Guangzhou, 510515, Guangdong, People's 
      Republic of China.
FAU - Wang, Junping
AU  - Wang J
AD  - State Key Laboratory of Trauma, Burns and Combined Injury, Chongqing Engineering 
      Research Center for Nanomedicine, Institute of Combined Injury, College of 
      Preventive Medicine, Third Military Medical University, Chongqing, 400038, 
      People's Republic of China.
FAU - Zhu, Fengxin
AU  - Zhu F
AD  - The State Key Laboratory of Organ Failure Research, National Clinical Research 
      Center of Kidney Disease, Key Laboratory of Organ Failure Research (Ministry of 
      Education), Division of Nephrology, Nanfang Hospital, Southern Medical 
      University, North Guangshou Avenue 1838, Guangzhou, 510515, Guangdong, People's 
      Republic of China. zhufengxin@126.com.
FAU - Nie, Jing
AU  - Nie J
AD  - The State Key Laboratory of Organ Failure Research, National Clinical Research 
      Center of Kidney Disease, Key Laboratory of Organ Failure Research (Ministry of 
      Education), Division of Nephrology, Nanfang Hospital, Southern Medical 
      University, North Guangshou Avenue 1838, Guangzhou, 510515, Guangdong, People's 
      Republic of China. niejing@smu.edu.cn.
LA  - eng
SI  - ClinicalTrials.gov/NCT00794885
PT  - Letter
PT  - Research Support, Non-U.S. Gov't
DEP - 20230727
PL  - England
TA  - J Hematol Oncol
JT  - Journal of hematology & oncology
JID - 101468937
RN  - EC 2.7.1.- (Phosphatidylinositol 3-Kinases)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - 9002-72-6 (Growth Hormone)
RN  - JL5DK93RCL (Melatonin)
SB  - IM
MH  - Humans
MH  - Mice
MH  - Animals
MH  - Thrombopoiesis/genetics
MH  - Megakaryocytes
MH  - Blood Platelets
MH  - Phosphatidylinositol 3-Kinases
MH  - Proto-Oncogene Proteins c-akt/genetics
MH  - Zebrafish
MH  - Growth Hormone/pharmacology
MH  - *Melatonin/pharmacology
MH  - *Hyperhomocysteinemia/complications
MH  - Cell Differentiation
PMC - PMC10373258
OTO - NOTNLM
OT  - Growth hormone
OT  - Hyperhomocysteinemia
OT  - Megakaryocyte
OT  - ScRNA-seq
OT  - Thrombopoiesis
COIS- The authors declare that they have no competing interests.
EDAT- 2023/07/28 01:08
MHDA- 2023/07/31 06:43
PMCR- 2023/07/27
CRDT- 2023/07/27 23:37
PHST- 2023/06/05 00:00 [received]
PHST- 2023/07/17 00:00 [accepted]
PHST- 2023/07/31 06:43 [medline]
PHST- 2023/07/28 01:08 [pubmed]
PHST- 2023/07/27 23:37 [entrez]
PHST- 2023/07/27 00:00 [pmc-release]
AID - 10.1186/s13045-023-01481-x [pii]
AID - 1481 [pii]
AID - 10.1186/s13045-023-01481-x [doi]
PST - epublish
SO  - J Hematol Oncol. 2023 Jul 27;16(1):84. doi: 10.1186/s13045-023-01481-x.