Identification and Comparison of Hyperglycemia-Induced Extracellular Vesicle Transcriptome in Different Mouse Stem Cells

Huang, Grace; Garikipati, Venkata Naga Srikanth; Zhou, Yan; Benedict, Cynthia; Houser, Steven R.; Koch, Walter J.; Kishore, Raj

doi:10.3390/cells9092098

Cited by 10 publications

(13 citation statements)

References 53 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Previously, we have reported that EPCs and other stem cells exposed to hyperglycemic culture conditions showed a dramatic alteration in EV RNA contents 14 . In this study, we performed comprehensive studies demonstrating that diabetes impairs EPC-EV functions both in vitro cell culture system and in vivo in two models of myocardial injury.…”

Section: Discussionmentioning

confidence: 98%

“…However, it is also being recognized that EV production, their cargo constituents and their functional activity depend largely on the pathophysiological environment of their parental cells 12 . Our previous studies have shown that external stimuli/stress such as inflammation and hyperglycemia changes EPC/stem cell-derived EV contents and functional properties 13 , 14 . In addition, EVs from diabetic plasma have been shown to be deficient in protecting cardiomyocytes 15 .…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Diabetes impairs cardioprotective function of endothelial progenitor cell-derived extracellular vesicles via H3K9Ac inhibition

Huang¹,

Cheng²,

Hildebrand³

et al. 2022

Theranostics

Self Cite

View full text Add to dashboard Cite

Background and Purpose: Myocardial infarction (MI) in diabetic patients results in higher mortality and morbidity. We and others have previously shown that bone marrow-endothelial progenitor cells (EPCs) promote cardiac neovascularization and attenuate ischemic injury. Lately, small extracellular vesicles (EVs) have emerged as major paracrine effectors mediating the benefits of stem cell therapy. Modest clinical outcomes of autologous cell-based therapies suggest diabetes-induced EPC dysfunction and may also reflect their EV derivatives. Moreover, studies suggest that post-translational histone modifications promote diabetes-induced vascular dysfunctions. Therefore, we tested the hypothesis that diabetic EPC-EVs may lose their post-injury cardiac reparative function by modulating histone modification in endothelial cells (ECs). Methods: We collected EVs from the culture medium of EPCs isolated from non-diabetic (db/+) and diabetic (db/db) mice and examined their effects on recipient ECs and cardiomyocytes in vitro, and their reparative function in permanent ligation of left anterior descending (LAD) coronary artery and ischemia/reperfusion (I/R) myocardial ischemic injuries in vivo . Results: Compared to db/+ EPC-EVs, db/db EPC-EVs promoted EC and cardiomyocyte apoptosis and repressed tube-forming capacity of ECs. In vivo , db/db EPC-EVs depressed cardiac function, reduced capillary density, and increased fibrosis compared to db/+ EPC-EV treatments after MI. Moreover, in the I/R MI model, db/+ EPC-EV-mediated acute cardio-protection was lost with db/db EPC-EVs, and db/db EPC-EVs increased immune cell infiltration, infarct area, and plasma cardiac troponin-I. Mechanistically, histone 3 lysine 9 acetylation (H3K9Ac) was significantly decreased in cardiac ECs treated with db/db EPC-EVs compared to db/+ EPC-EVs. The H3K9Ac chromatin immunoprecipitation sequencing (ChIP-Seq) results further revealed that db/db EPC-EVs reduced H3K9Ac level on angiogenic, cell survival, and proliferative genes in cardiac ECs. We found that the histone deacetylase (HDAC) inhibitor, valproic acid (VPA), partly restored diabetic EPC-EV-impaired H3K9Ac levels, tube formation and viability of ECs, and enhanced cell survival and proliferative genes, Pdgfd and Sox12 , expression. Moreover, we observed that VPA treatment improved db/db EPC-mediated post-MI cardiac repair and functions. Conclusions: Our findings unravel that diabetes impairs EPC-EV reparative function in the ischemic heart, at least partially, through HDACs-mediated H3K9Ac downregulation leading to transcriptional suppression of angiogenic, proliferative and cell survival genes in recipient cardiac ECs. Thus, HDAC inhibitors may potentially be used to restore the function of diabetic EPC and other stem cells for autologous cell therapy applications.

show abstract

Section: Discussionmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

Diabetes impairs cardioprotective function of endothelial progenitor cell-derived extracellular vesicles via H3K9Ac inhibition

Huang¹,

Cheng²,

Hildebrand³

et al. 2022

Theranostics

Self Cite

View full text Add to dashboard Cite

show abstract

“…Although diabetes does not affect the size and concentration of exosomes, they have a significant effect in altering the exosomes cargoes, thereby affecting the functional ability of exosomes [ 31 , 99 , 110 , 111 ]. Kim et al attributed dysregulated glucose metabolism to the altered circulating exosomal miRNA profile in obese diabetic individuals in comparison to healthy controls [ 112 ].…”

Section: Exosomes In Dhd and Their Therapeutic Potentialmentioning

confidence: 99%

Exosomal microRNAs in diabetic heart disease

Chandrasekera

Katare

2022

Cardiovasc Diabetol

View full text Add to dashboard Cite

Diabetes is a metabolic disorder that affects millions of people worldwide. Diabetic heart disease (DHD) comprises coronary artery disease, heart failure, cardiac autonomic neuropathy, peripheral arterial disease, and diabetic cardiomyopathy. The onset and progression of DHD have been attributed to molecular alterations in response to hyperglycemia in diabetes. In this context, microRNAs (miRNAs) have been demonstrated to have a significant role in the development and progression of DHD. In addition to their effects on the host cells, miRNAs can be released into circulation after encapsulation within the exosomes. Exosomes are extracellular nanovesicles ranging from 30 to 180 nm in diameter secreted by all cell types. They carry diverse cargos that are altered in response to various conditions in their parent cells. Exosomal miRNAs have been extensively studied in recent years due to their role and therapeutic potential in DHD. This review will first provide an overview of exosomes, their biogenesis and function, followed by the role of exosomes in cardiovascular disease and then focuses on the known role of exosomes and associated miRNAs in DHD.

show abstract

“…Transcriptomic analysis of EVs derived from endothelial progenitor cells (EPCs), cardiac progenitor cells (CPCs), and cortical bone stem cells revealed the differential and similar composition of various mRNAs, miRNAs, and other noncoding RNAs [ 32 ]. Interestingly, this composition differed when parent cells were exposed to hyperglycemic conditions, implying selective genetic compositions based on the microenvironment or disease condition [ 32 ]. A class of long noncoding RNAs resulting from back splicing in the lariat splicing event process entrapped in exosomes could play a prominent role in CVD remodeling [ 22 ].…”

Section: Biology Of Exosomesmentioning

confidence: 99%

Unfathomed Nanomessages to the Heart: Translational Implications of Stem Cell-Derived, Progenitor Cell Exosomes in Cardiac Repair and Regeneration

Thej

Kishore

2021

Cells

Self Cite

View full text Add to dashboard Cite

Exosomes formed from the endosomal membranes at the lipid microdomains of multivesicular bodies (MVBs) have become crucial structures responsible for cell communication. This paracrine communication system between a myriad of cell types is essential for maintaining homeostasis and influencing various biological functions in immune, vasculogenic, and regenerative cell types in multiple organs in the body, including, but not limited to, cardiac cells and tissues. Characteristically, exosomes are identifiable by common proteins that participate in their biogenesis; however, many different proteins, mRNA, miRNAs, and lipids, have been identified that mediate intercellular communication and elicit multiple functions in other target cells. Although our understanding of exosomes is still limited, the last decade has seen a steep surge in translational studies involving the treatment of cardiovascular diseases with cell-free exosome fractions from cardiomyocytes (CMs), cardiosphere-derived cells (CDCs), endothelial cells (ECs), mesenchymal stromal cells (MSCs), or their combinations. However, most primary cells are difficult to culture in vitro and to generate sufficient exosomes to treat cardiac ischemia or promote cardiac regeneration effectively. Pluripotent stem cells (PSCs) offer the possibility of an unlimited supply of either committed or terminally differentiated cells and their exosomes for treating cardiovascular diseases (CVDs). This review discusses the promising prospects of treating CVDs using exosomes from cardiac progenitor cells (CPCs), endothelial progenitor cells (EPCs), MSCs, and cardiac fibroblasts derived from PSCs.

show abstract

Identification and Comparison of Hyperglycemia-Induced Extracellular Vesicle Transcriptome in Different Mouse Stem Cells

Cited by 10 publications

References 53 publications

Diabetes impairs cardioprotective function of endothelial progenitor cell-derived extracellular vesicles via H3K9Ac inhibition

Diabetes impairs cardioprotective function of endothelial progenitor cell-derived extracellular vesicles via H3K9Ac inhibition

Exosomal microRNAs in diabetic heart disease

Unfathomed Nanomessages to the Heart: Translational Implications of Stem Cell-Derived, Progenitor Cell Exosomes in Cardiac Repair and Regeneration

Contact Info

Product

Resources

About