Hypoxia-stressed cardiomyocytes promote early cardiac differentiation of cardiac stem cells through HIF-1/Jagged1/Notch1 signaling.
10.1016/j.apsb.2018.06.003
- Author:
Keke WANG
1
;
Ranran DING
1
;
Yanping HA
1
;
Yanan JIA
1
;
Xiaomin LIAO
1
;
Sisi WANG
1
;
Rujia LI
1
;
Zhihua SHEN
1
;
Hui XIONG
1
;
Junli GUO
2
;
Wei JIE
1
Author Information
1. Department of Pathology, Guangdong Medical University, Zhanjiang 52 4023, China.
2. Cardiovascular Institute of First Affiliated Hospital, Hainan Medical University, Haikou 570102, China.
- Publication Type:Journal Article
- Keywords:
BMSCs, bone marrow stem cells;
BrdU, 5-bromo-2′-deoxyuridine;
CMs, cardiomyocytes;
CSCs, cardiac stem cells;
Cardiac stem cell;
Cardiomyocyte, Co-culture;
Cell differentiation;
DAPI, 4′,6-diamidino-2-phenylindole;
DMSO, dimethyl sulfoxide;
ERK, extracellular signal-regulated kinase;
FBS, fetal bovine serum;
FITC, fluorescein isothiocyanate;
GFP, green fluorescent protein;
HIF-1α, hypoxia-inducible factor 1α;
HRE, hypoxia responsive element;
Hypoxia;
JAK, Janus kinase;
JNK, c-Jun N-terminal kinase;
MACS, magnetic-activated cell sorting;
MI, myocardial infarction;
MOI, multiplicity of infection;
N-ICD, notch intracellular domain;
NF-κB, nuclear factor κB;
Notch1 signaling;
PBS, phosphate buffer saline;
PE, phycoerythrin;
RT-PCR, reverse transcription PCR;
STAT3, signal transducer and activator of transcription 3;
YC-1, 3-(5′-hydroxymethyl-2′-furyl)-1-benzyl-indazole;
qPCR, quantitative PCR;
vWF, von Willebrand factor
- From:
Acta Pharmaceutica Sinica B
2018;8(5):795-804
- CountryChina
- Language:English
-
Abstract:
Hypoxia is beneficial for the differentiation of stem cells transplanted for myocardial injury, but mechanisms underlying this benefit remain unsolved. Here, we report the impact of hypoxia-induced Jagged1 expression in cardiomyocytes (CMs) for driving the differentiation of cardiac stem cells (CSCs). Forced hypoxia-inducible factor 1 (HIF-1) expression and physical hypoxia (5% O) treatment could induce Jagged1 expression in neonatal rat CMs. Pharmacological inhibition of HIF-1 by YC-1 attenuated hypoxia-promoted Jagged1 expression in CMs. An ERK inhibitor (PD98059), but not inhibitors of JNK (SP600125), Notch (DAPT), NF-B (PTDC), JAK (AG490), or STAT3 (Stattic) suppressed hypoxia-induced Jagged1 protein expression in CMs. c-Kit CSCs isolated from neonatal rat hearts using a magnetic-activated cell sorting method expressed GATA4, SM22 or vWF, but not Nkx2.5 and cTnI. Moreover, 87.3% of freshly isolated CSCs displayed Notch1 receptor expression. Direct co-culture of CMs with BrdU-labeled CSCs enhanced CSCs differentiation, as evidenced by an increased number of BrdU/Nkx2.5 cells, while intermittent hypoxia for 21 days promoted co-culture-triggered differentiation of CSCs into CM-like cells. Notably, YC-1 and DAPT attenuated hypoxia-induced differentiation. Our results suggest that hypoxia induces Jagged1 expression in CMs primarily through ERK signaling, and facilitates early cardiac lineage differentiation of CSCs in CM/CSC co-cultures HIF-1/Jagged1/Notch signaling.
