miR-30e targets IGF2-regulated osteogenesis in bone marrow-derived mesenchymal stem cells, aortic smooth muscle cells, and ApoE-/- mice

Wen Ding, Jihe Li, Jayanti Singh, Razan Alif, Roberto I. Vazquez-Padron, Samirah A. Gomes, Joshua M. Hare, Lina A. Shehadeh

Research output: Contribution to journalArticle

Abstract

Aims Activation of an osteogenic transcriptional program contributes to the initiation of aortic calcification in atherosclerosis. The role of microRNAs in regulating aortic calcification is understudied. We tested the hypothesis that miR-30e regulates an osteogenic program in bone marrow-derived mesenchymal stem cells (MSCs), aortic smooth muscle cells (SMCs), and ApoE-/- mice. Methods and results In aortas of wild-type mice, we found that miR-30e is highly expressed in medial SMCs. In aortas of old ApoE-/- mice, we found that miR-30e transcripts are down-regulated in an inverse relation to the osteogenic markers Runx2, Opn, and Igf2. In vitro, miR-30e over-expression reduced the proliferation of MSCs and SMCs while increasing adipogenic differentiation of MSCs and smooth muscle differentiation of SMCs. In MSCs and SMCs over-expressing miR-30e, microarrays and qPCR showed repression of an osteogenic gene panel including Igf2. Inhibiting miR-30e in MSCs increased Igf2 transcripts. In SMCs, IGF2 recombinant protein rescued miR-30e-repressed osteogenic differentiation. Luciferase and mutagenesis assays showed binding of miR-30e to a novel and essential site at the 3'UTR of Igf2. In ApoE-/- mice, injections of antimiR-30e oligos increased Igf2 expression in the aortas and livers and significantly enhanced OPN protein expression and calcium deposition in aortic valves. Conclusion miR-30e represses the osteogenic program in MSCs and SMCs by targeting IGF2 and drives their differentiation into adipogenic or smooth muscle lineage, respectively. Our data suggest that down-regulation of miR-30e in aortas with age and atherosclerosis triggers vascular calcification. The miR-30e pathway plays an important regulatory role in vascular diseases.

Original languageEnglish (US)
Pages (from-to)131-142
Number of pages12
JournalCardiovascular Research
Volume106
Issue number1
DOIs
StatePublished - Apr 1 2015
Externally publishedYes

Fingerprint

Apolipoproteins E
Mesenchymal Stromal Cells
Osteogenesis
Smooth Muscle Myocytes
Bone Marrow
Aorta
Smooth Muscle
Atherosclerosis
Vascular Calcification
3' Untranslated Regions
Luciferases
MicroRNAs
Aortic Valve
Vascular Diseases
Recombinant Proteins
Mutagenesis
Transcriptional Activation
Down-Regulation
Calcium
Injections

Keywords

  • Calcification
  • Mesenchymal stem cells
  • MicroRNA-30e
  • Osteogenesis
  • Smooth muscle cells

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)
  • Physiology

Cite this

miR-30e targets IGF2-regulated osteogenesis in bone marrow-derived mesenchymal stem cells, aortic smooth muscle cells, and ApoE-/- mice. / Ding, Wen; Li, Jihe; Singh, Jayanti; Alif, Razan; Vazquez-Padron, Roberto I.; Gomes, Samirah A.; Hare, Joshua M.; Shehadeh, Lina A.

In: Cardiovascular Research, Vol. 106, No. 1, 01.04.2015, p. 131-142.

Research output: Contribution to journalArticle

Ding, W, Li, J, Singh, J, Alif, R, Vazquez-Padron, RI, Gomes, SA, Hare, JM & Shehadeh, LA 2015, 'miR-30e targets IGF2-regulated osteogenesis in bone marrow-derived mesenchymal stem cells, aortic smooth muscle cells, and ApoE-/- mice', Cardiovascular Research, vol. 106, no. 1, pp. 131-142. https://doi.org/10.1093/cvr/cvv030
Ding, Wen ; Li, Jihe ; Singh, Jayanti ; Alif, Razan ; Vazquez-Padron, Roberto I. ; Gomes, Samirah A. ; Hare, Joshua M. ; Shehadeh, Lina A. / miR-30e targets IGF2-regulated osteogenesis in bone marrow-derived mesenchymal stem cells, aortic smooth muscle cells, and ApoE-/- mice. In: Cardiovascular Research. 2015 ; Vol. 106, No. 1. pp. 131-142.
@article{64e4bc6421a0492d8e7e581a25f6b853,
title = "miR-30e targets IGF2-regulated osteogenesis in bone marrow-derived mesenchymal stem cells, aortic smooth muscle cells, and ApoE-/- mice",
abstract = "Aims Activation of an osteogenic transcriptional program contributes to the initiation of aortic calcification in atherosclerosis. The role of microRNAs in regulating aortic calcification is understudied. We tested the hypothesis that miR-30e regulates an osteogenic program in bone marrow-derived mesenchymal stem cells (MSCs), aortic smooth muscle cells (SMCs), and ApoE-/- mice. Methods and results In aortas of wild-type mice, we found that miR-30e is highly expressed in medial SMCs. In aortas of old ApoE-/- mice, we found that miR-30e transcripts are down-regulated in an inverse relation to the osteogenic markers Runx2, Opn, and Igf2. In vitro, miR-30e over-expression reduced the proliferation of MSCs and SMCs while increasing adipogenic differentiation of MSCs and smooth muscle differentiation of SMCs. In MSCs and SMCs over-expressing miR-30e, microarrays and qPCR showed repression of an osteogenic gene panel including Igf2. Inhibiting miR-30e in MSCs increased Igf2 transcripts. In SMCs, IGF2 recombinant protein rescued miR-30e-repressed osteogenic differentiation. Luciferase and mutagenesis assays showed binding of miR-30e to a novel and essential site at the 3'UTR of Igf2. In ApoE-/- mice, injections of antimiR-30e oligos increased Igf2 expression in the aortas and livers and significantly enhanced OPN protein expression and calcium deposition in aortic valves. Conclusion miR-30e represses the osteogenic program in MSCs and SMCs by targeting IGF2 and drives their differentiation into adipogenic or smooth muscle lineage, respectively. Our data suggest that down-regulation of miR-30e in aortas with age and atherosclerosis triggers vascular calcification. The miR-30e pathway plays an important regulatory role in vascular diseases.",
keywords = "Calcification, Mesenchymal stem cells, MicroRNA-30e, Osteogenesis, Smooth muscle cells",
author = "Wen Ding and Jihe Li and Jayanti Singh and Razan Alif and Vazquez-Padron, {Roberto I.} and Gomes, {Samirah A.} and Hare, {Joshua M.} and Shehadeh, {Lina A.}",
year = "2015",
month = "4",
day = "1",
doi = "10.1093/cvr/cvv030",
language = "English (US)",
volume = "106",
pages = "131--142",
journal = "Cardiovascular Research",
issn = "0008-6363",
publisher = "Oxford University Press",
number = "1",

}

TY - JOUR

T1 - miR-30e targets IGF2-regulated osteogenesis in bone marrow-derived mesenchymal stem cells, aortic smooth muscle cells, and ApoE-/- mice

AU - Ding, Wen

AU - Li, Jihe

AU - Singh, Jayanti

AU - Alif, Razan

AU - Vazquez-Padron, Roberto I.

AU - Gomes, Samirah A.

AU - Hare, Joshua M.

AU - Shehadeh, Lina A.

PY - 2015/4/1

Y1 - 2015/4/1

N2 - Aims Activation of an osteogenic transcriptional program contributes to the initiation of aortic calcification in atherosclerosis. The role of microRNAs in regulating aortic calcification is understudied. We tested the hypothesis that miR-30e regulates an osteogenic program in bone marrow-derived mesenchymal stem cells (MSCs), aortic smooth muscle cells (SMCs), and ApoE-/- mice. Methods and results In aortas of wild-type mice, we found that miR-30e is highly expressed in medial SMCs. In aortas of old ApoE-/- mice, we found that miR-30e transcripts are down-regulated in an inverse relation to the osteogenic markers Runx2, Opn, and Igf2. In vitro, miR-30e over-expression reduced the proliferation of MSCs and SMCs while increasing adipogenic differentiation of MSCs and smooth muscle differentiation of SMCs. In MSCs and SMCs over-expressing miR-30e, microarrays and qPCR showed repression of an osteogenic gene panel including Igf2. Inhibiting miR-30e in MSCs increased Igf2 transcripts. In SMCs, IGF2 recombinant protein rescued miR-30e-repressed osteogenic differentiation. Luciferase and mutagenesis assays showed binding of miR-30e to a novel and essential site at the 3'UTR of Igf2. In ApoE-/- mice, injections of antimiR-30e oligos increased Igf2 expression in the aortas and livers and significantly enhanced OPN protein expression and calcium deposition in aortic valves. Conclusion miR-30e represses the osteogenic program in MSCs and SMCs by targeting IGF2 and drives their differentiation into adipogenic or smooth muscle lineage, respectively. Our data suggest that down-regulation of miR-30e in aortas with age and atherosclerosis triggers vascular calcification. The miR-30e pathway plays an important regulatory role in vascular diseases.

AB - Aims Activation of an osteogenic transcriptional program contributes to the initiation of aortic calcification in atherosclerosis. The role of microRNAs in regulating aortic calcification is understudied. We tested the hypothesis that miR-30e regulates an osteogenic program in bone marrow-derived mesenchymal stem cells (MSCs), aortic smooth muscle cells (SMCs), and ApoE-/- mice. Methods and results In aortas of wild-type mice, we found that miR-30e is highly expressed in medial SMCs. In aortas of old ApoE-/- mice, we found that miR-30e transcripts are down-regulated in an inverse relation to the osteogenic markers Runx2, Opn, and Igf2. In vitro, miR-30e over-expression reduced the proliferation of MSCs and SMCs while increasing adipogenic differentiation of MSCs and smooth muscle differentiation of SMCs. In MSCs and SMCs over-expressing miR-30e, microarrays and qPCR showed repression of an osteogenic gene panel including Igf2. Inhibiting miR-30e in MSCs increased Igf2 transcripts. In SMCs, IGF2 recombinant protein rescued miR-30e-repressed osteogenic differentiation. Luciferase and mutagenesis assays showed binding of miR-30e to a novel and essential site at the 3'UTR of Igf2. In ApoE-/- mice, injections of antimiR-30e oligos increased Igf2 expression in the aortas and livers and significantly enhanced OPN protein expression and calcium deposition in aortic valves. Conclusion miR-30e represses the osteogenic program in MSCs and SMCs by targeting IGF2 and drives their differentiation into adipogenic or smooth muscle lineage, respectively. Our data suggest that down-regulation of miR-30e in aortas with age and atherosclerosis triggers vascular calcification. The miR-30e pathway plays an important regulatory role in vascular diseases.

KW - Calcification

KW - Mesenchymal stem cells

KW - MicroRNA-30e

KW - Osteogenesis

KW - Smooth muscle cells

UR - http://www.scopus.com/inward/record.url?scp=84926679819&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84926679819&partnerID=8YFLogxK

U2 - 10.1093/cvr/cvv030

DO - 10.1093/cvr/cvv030

M3 - Article

C2 - 25678587

AN - SCOPUS:84926679819

VL - 106

SP - 131

EP - 142

JO - Cardiovascular Research

JF - Cardiovascular Research

SN - 0008-6363

IS - 1

ER -