Endothelial‑like cells differentiated from mesenchymal stem cells attenuate neointimal hyperplasia after vascular injury

Xu,Jianzhong; Wu,Duojiao; Yang,Yan; Ji,Kaida; Gao,Pingjin

doi:10.3892/mmr.2016.5799

Endothelial‑like cells differentiated from mesenchymal stem cells attenuate neointimal hyperplasia after vascular injury

Authors:
- Jianzhong Xu
- Duojiao Wu
- Yan Yang
- Kaida Ji
- Pingjin Gao
View Affiliations

Affiliations: State Key Laboratory of Medical Genomics, Shanghai Key Laboratory of Vascular Biology, Department of Hypertension, Shanghai Institute of Hypertension, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200025, P.R. China
Published online on: October 5, 2016 https://doi.org/10.3892/mmr.2016.5799
Pages: 4830-4836
Copyright: © Xu et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

The present study investigated the contribution of bone marrow-derived mesenchymal stem cells (BM‑MSCs) to neointimal formation, and whether endothelial‑like cells (ELCs) differentiated from BM‑MSCs could attenuate intimal hyperplasia following vascular injury. BM‑MSCs were isolated from rat femurs and tibias and expanded ex vivo. Differentiation into ELCs was induced by cultivation in the presence of 50 ng/ml vascular endothelial growth factor (VEGF). MSCs and ELCs were labeled with BrdU and injected via the femoral vein on the day of a balloon‑induced carotid artery injury. Carotid artery morphology and histology were examined using ultrasound biomicroscopy and immunohistochemistry. Flow cytometry analysis measured CD31 and CD34 expression, and immunofluorescence analysis measured von Willebrand factor and VEGF receptor 2 expression in ELCs. Ultrasound biomicroscopy observed a significantly increased intima‑media thickness in the phosphate‑buffered saline (PBS) and BM‑MSCs groups compared with the ELCs group. Intima/media ratios were significantly reduced in the ELCs group compared with the PBS and BM‑MSCs groups. At 4 weeks of administration, the cells labeled with BrdU were abundantly located in the adventitial region and neointima. MSCs were able to differentiate into ELCs in vitro. Cell therapy with BM‑MSCs was not able to attenuate neointima thickness, however transplantation with ELCs significantly suppressed intimal hyperplasia following vascular injury.

View Figures

View References

1	Williams AR and Hare JM: Mesenchymal stem cells: Biology, pathophysiology, translational findings, and therapeutic implications for cardiac disease. Circ Res. 109:923–940. 2011. View Article : Google Scholar : PubMed/NCBI
2	Oswald J, Boxberger S, Jørgensen B, Feldmann S, Ehninger G, Bornhäuser M and Werner C: Mesenchymal stem cells can be differentiated into endothelial cells in vitro. Stem Cells. 22:377–384. 2004. View Article : Google Scholar : PubMed/NCBI
3	Silva GV, Litovsky S, Assad JA, Sousa AL, Martin BJ, Vela D, Coulter SC, Lin J, Ober J, Vaughn WK, et al: Mesenchymal stem cells differentiate into an endothelial phenotype, enhance vascular density, and improve heart function in a canine chronic ischemia model. Circulation. 111:150–156. 2005. View Article : Google Scholar : PubMed/NCBI
4	Suzuki S, Narita Y, Yamawaki A, Murase Y, Satake M, Mutsuga M, Okamoto H, Kagami H, Ueda M and Ueda Y: Effects of extracellular matrix on differentiation of human bone marrow-derived mesenchymal stem cells into smooth muscle cell lineage: Utility for cardiovascular tissue engineering. Cells Tissues Organs. 191:269–280. 2010. View Article : Google Scholar : PubMed/NCBI
5	Tang Z, Wang A, Yuan F, Yan Z, Liu B, Chu JS, Helms JA and Li S: Differentiation of multipotent vascular stem cells contributes to vascular diseases. Nat Commun. 3:8752012. View Article : Google Scholar : PubMed/NCBI
6	Forte A, Finicelli M, Mattia M, Berrino L, Rossi F, De Feo M, Cotrufo M, Cipollaro M, Cascino A and Galderisi U: Mesenchymal stem cells effectively reduce surgically induced stenosis in rat carotids. J Cell Physiol. 217:789–799. 2008. View Article : Google Scholar : PubMed/NCBI
7	Forte A, Rinaldi B, Sodano L, Berrino L, Rossi F, Finicelli M, Grossi M, Cobellis G, Botti C, De Feo M, et al: Stem cell therapy for arterial restenosis: Potential parameters contributing to the success of bone marrow-derived mesenchymal stromal cells. Cardiovasc Drugs Ther. 26:9–21. 2012. View Article : Google Scholar : PubMed/NCBI
8	Shoji M, Oskowitz A, Malone CD, Prockop DJ and Pochampally R: Human mesenchymal stromal cells (MSCs) reduce neointimal hyperplasia in a mouse model of flow-restriction by transient suppression of anti-inflammatory cytokines. J Atheroscler Thromb. 18:464–474. 2011. View Article : Google Scholar : PubMed/NCBI
9	Feng J, Liu JP, Miao L, He GX, Li D, Wang HD and Jing T: Conditional expression of the type 2 angiotensin ii receptor in mesenchymal stem cells inhibits neointimal formation after arterial injury. J Cardiovasc Transl Res. 7:635–643. 2014. View Article : Google Scholar : PubMed/NCBI
10	Wang CH, Cherng WJ, Yang NI, Kuo LT, Hsu CM, Yeh HI, Lan YJ, Yeh CH and Stanford WL: Late-outgrowth endothelial cells attenuate intimal hyperplasia contributed by mesenchymal stem cells after vascular injury. Arterioscler Thromb Vasc Biol. 28:54–60. 2008. View Article : Google Scholar : PubMed/NCBI
11	Liao J, Chen X, Li Y, Ge Z, Duan H, Zou Y and Ge J: Transfer of bone-marrow-derived mesenchymal stem cells influences vascular remodeling and calcification after balloon injury in hyperlipidemic rats. J Biomed Biotechnol. 2012:1652962012. View Article : Google Scholar : PubMed/NCBI
12	Zhang FB, Li L, Fang B, Zhu DL, Yang HT and Gao PJ: Passage-restricted differentiation potential of mesenchymal stem cells into cardiomyocyte-like cells. Biochem Biophys Res Commun. 336:784–792. 2005. View Article : Google Scholar : PubMed/NCBI
13	Kim S, Kawamura M, Wanibuchi H, Ohta K, Hamaguchi A, Omura T, Yukimura T, Miura K and Iwao H: Angiotensin II type 1 receptor blockade inhibits the expression of immediate-early genes and fibronectin in rat injured artery. Circulation. 92:88–95. 1995. View Article : Google Scholar : PubMed/NCBI
14	Pankajakshan D, Kansal V and Agrawal DK: In vitro differentiation of bone marrow derived porcine mesenchymal stem cells to endothelial cells. J Tissue Eng Regen Med. 7:911–920. 2013. View Article : Google Scholar : PubMed/NCBI
15	Pittenger MF, Mackay AM, Beck SC, Jaiswal RK, Douglas R, Mosca JD, Moorman MA, Simonetti DW, Craig S and Marshak DR: Multilineage potential of adult human mesenchymal stem cells. Science. 284:143–147. 1999. View Article : Google Scholar : PubMed/NCBI
16	Gan LM, Grönros J, Hägg U, Wikström J, Theodoropoulos C, Friberg P and Fritsche-Danielson R: Non-invasive real-time imaging of atherosclerosis in mice using ultrasound biomicroscopy. Atherosclerosis. 190:313–320. 2007. View Article : Google Scholar : PubMed/NCBI
17	Wu DJ, Xu JZ, Wu YJ, Jean-Charles L, Xiao B, Gao PJ and Zhu DL: Effects of fasudil on early atherosclerotic plaque formation and established lesion progression in apolipoprotein E-knockout mice. Atherosclerosis. 207:68–73. 2009. View Article : Google Scholar : PubMed/NCBI
18	Hillebrands JL, Klatter FA, van den Hurk BM, Popa ER, Nieuwenhuis P and Rozing J: Origin of neointimal endothelium and alpha-actin-positive smooth muscle cells in transplant arteriosclerosis. J Clin Invest. 107:1411–1422. 2001. View Article : Google Scholar : PubMed/NCBI
19	Grimm PC, Nickerson P, Jeffery J, Savani RC, Gough J, McKenna RM, Stern E and Rush DN: Neointimal and tubulointerstitial infiltration by recipient mesenchymal cells in chronic renal-allograft rejection. N Engl J Med. 345:93–97. 2001. View Article : Google Scholar : PubMed/NCBI
20	Li M, Li S, Yu L, Wu J, She T, Gan Y, Hu Z, Liao W and Xia H: Bone mesenchymal stem cells contributed to the neointimal formation after arterial injury. PLoS One. 8:e827432013. View Article : Google Scholar : PubMed/NCBI
21	Yue WM, Liu W, Bi YW, He XP, Sun WY, Pang XY, Gu XH and Wang XP: Mesenchymal stem cells differentiate into an endothelial phenotype, reduce neointimal formation, and enhance endothelial function in a rat vein grafting model. Stem Cells Dev. 17:785–793. 2008. View Article : Google Scholar : PubMed/NCBI
22	Kerkelä E, Hakkarainen T, Mäkelä T, Raki M, Kambur O, Kilpinen L, Nikkilä J, Lehtonen S, Ritamo I, Pernu R, et al: Transient proteolytic modification of mesenchymal stromal cells increases lung clearance rate and targeting to injured tissue. Stem Cells Transl Med. 2:510–520. 2013. View Article : Google Scholar : PubMed/NCBI
23	Psaltis PJ, Puranik AS, Spoon DB, Chue CD, Hoffman SJ, Witt TA, Delacroix S, Kleppe LS, Mueske CS, Pan S, et al: Characterization of a resident population of adventitial macrophage progenitor cells in postnatal vasculature. Circ Res. 115:364–375. 2014. View Article : Google Scholar : PubMed/NCBI
24	Chen Y, Wong MM, Campagnolo P, Simpson R, Winkler B, Margariti A, Hu Y and Xu Q: Adventitial stem cells in vein grafts display multilineage potential that contributes to neointimal formation. Arterioscler Thromb Vasc Biol. 33:1844–1851. 2013. View Article : Google Scholar : PubMed/NCBI
25	Grudzinska MK, Kurzejamska E, Bojakowski K, Soin J, Lehmann MH, Reinecke H, Murry CE, Soderberg-Naucler C and Religa P: Monocyte chemoattractant protein 1-mediated migration of mesenchymal stem cells is a source of intimal hyperplasia. Arterioscler Thromb Vasc Biol. 33:1271–1279. 2013. View Article : Google Scholar : PubMed/NCBI