Adenovirus-mediated transfer of hepatocyte growth factor gene to human dental pulp stem cells under good manufacturing practice improves their potential for periodontal regeneration in swine

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Abstract

Introduction

Periodontitis is one of the most widespread infectious diseases in humans. We previously promoted significant periodontal tissue regeneration in swine models with the transplantation of autologous periodontal ligament stem cells (PDLSCs) and PDLSC sheet. We also promoted periodontal tissue regeneration in a rat model with a local injection of allogeneic bone marrow mesenchymal stem cells. The purpose of the present study is to investigate the roles of the hepatocyte growth factor (HGF) and human dental pulp stem cells (DPSCs) in periodontal tissue regeneration in swine.

Method

In the present study, we transferred an adenovirus that carried HGF gene into human DPSCs (HGF-hDPSCs) under good manufacturing practice (GMP) conditions. These cells were then transplanted into a swine model for periodontal regeneration. Twenty miniature pigs were used to generate periodontitis with bone defect of 5 mm in width, 7 mm in length, and 3 mm in depth. After 12 weeks, clinical, radiological, quantitative and histological assessment of regenerated periodontal tissues was performed to compare periodontal regeneration in swine treated with cell implantation.

Results

Our study showed that injecting HGF-hDPSCs into this large animal model could significantly improve periodontal bone regeneration and soft tissue healing. A hDPSC or HGF-hDPSC sheet showed superior periodontal tissue regeneration compared to the injection of dissociated cells. However, the sheets required surgical placement; thus, they were suitable for surgically-managed periodontitis treatments. The adenovirus-mediated transfer of the HGF gene markedly decreased hDPSC apoptosis in a hypoxic environment or in serum-free medium, and it increased blood vessel regeneration.

Conclusion

This study indicated that HGF-hDPSCs produced under GMP conditions significantly improved periodontal bone regeneration in swine; thus, this method represents a potential clinical application for periodontal regeneration.

Electronic supplementary material

The online version of this article (doi:10.1186/s13287-015-0244-5) contains supplementary material, which is available to authorized users.

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Most cited references 25

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Hepatocyte growth factor is a potent angiogenic factor which stimulates endothelial cell motility and growth

G Gaudino, MF Di Renzo, L Naldini … (1992)

Hepatocyte Growth Factor (HGF, also known as Scatter Factor) is a powerful mitogen or motility factor in different cells, acting through the tyrosine kinase receptor encoded by the MET protooncogene. Endothelial cells express the MET gene and expose at the cell surface the mature protein (p190MET) made of a 50 kD (alpha) subunit disulfide linked to a 145-kD (beta) subunit. HGF binding to endothelial cells identifies two sites with different affinities. The higher affinity binding site (Kd = 0.35 nM) corresponds to the p190MET receptor. Sub- nanomolar concentrations of HGF, but not of a recombinant inactive precursor, stimulate the receptor kinase activity, cell proliferation and motility. HGF induces repairs of a wound in endothelial cell monolayer. HGF stimulates the scatter of endothelial cells grown on three-dimensional collagen gels, inducing an elongated phenotype. In the rabbit cornea, highly purified HGF promotes neovascularization at sub-nanomolar concentrations. HGF lacks activities related to hemostasis-thrombosis, inflammation and endothelial cells accessory functions. These data show that HGF is an in vivo potent angiogenic factor and in vitro induces endothelial cells to proliferate and migrate.

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Mesenchymal stem cell implantation in a swine myocardial infarct model: engraftment and functional effects.

Jay G Shake, Peter J. Gruber, William A Baumgartner … (2002)

A novel therapeutic option for the treatment of acute myocardial infarction involves the use of mesenchymal stem cells (MSCs). The purpose of this study was to investigate whether implantation of autologous MSCs results in sustained engraftment, myogenic differentiation, and improved cardiac function in a swine myocardial infarct model. MSCs were isolated and expanded from bone marrow aspirates of 14 domestic swine. A 60-minute left anterior descending artery occlusion was used to produce anterior wall infarction. Piezoelectric crystals were placed within the ischemic region for measurement of regional wall thickness and contractile function. Two weeks later animals autologous, Di-I-labeled MSCs (6 x 10(7)) were implanted into the infarct by direct injection. Hemodynamic and functional measurements were obtained weekly until the time of sacrifice. Immunohistochemistry was used to assess MSC engraftment and myogenic differentiation. Microscopic analysis showed robust engraftment of MSCs in all treated animals. Expression of muscle-specific proteins was seen as early as 2 weeks and could be identified in all animals at sacrifice. The degree of contractile dysfunction was significantly attenuated at 4 weeks in animals implanted with MSCs (5.4% +/- 2.2% versus -3.37% +/- 2.7% in control). In addition, the extent of wall thinning after myocardial infarction was markedly reduced in treated animals. Mesenchymal stem cells are capable of engraftment in host myocardium, demonstrate expression of muscle specific proteins, and may attenuate contractile dysfunction and pathologic thinning in this model of left ventricular wall infarction. MSC cardiomyoplasty may have significant clinical potential in attenuating the pathology associated with myocardial infarction.

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Cardiac stem cells possess growth factor-receptor systems that after activation regenerate the infarcted myocardium, improving ventricular function and long-term survival.

Konrad Urbanek, Marcello Rota, Stefano Cascapera … (2005)

Cardiac stem cells and early committed cells (CSCs-ECCs) express c-Met and insulin-like growth factor-1 (IGF-1) receptors and synthesize and secrete the corresponding ligands, hepatocyte growth factor (HGF) and IGF-1. HGF mobilizes CSCs-ECCs and IGF-1 promotes their survival and proliferation. Therefore, HGF and IGF-1 were injected in the hearts of infarcted mice to favor, respectively, the translocation of CSCs-ECCs from the surrounding myocardium to the dead tissue and the viability and growth of these cells within the damaged area. To facilitate migration and homing of CSCs-ECCs to the infarct, a growth factor gradient was introduced between the site of storage of primitive cells in the atria and the region bordering the infarct. The newly-formed myocardium contained arterioles, capillaries, and functionally competent myocytes that with time increased in size, improving ventricular performance at healing and long thereafter. The volume of regenerated myocytes was 2200 microm3 at 16 days after treatment and reached 5100 microm3 at 4 months. In this interval, nearly 20% of myocytes reached the adult phenotype, varying in size from 10,000 to 20,000 microm3. Moreover, there were 43+/-13 arterioles and 155+/-48 capillaries/mm2 myocardium at 16 days, and 31+/-6 arterioles and 390+/-56 capillaries at 4 months. Myocardial regeneration induced increased survival and rescued animals with infarcts that were up to 86% of the ventricle, which are commonly fatal. In conclusion, the heart has an endogenous reserve of CSCs-ECCs that can be activated to reconstitute dead myocardium and recover cardiac function.

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Author and article information

Contributors

Yu Cao: caoyu_bj@163.com

Zhenhai Liu: 13683684505@163.com

Yilin Xie: kazaf-helen@qq.com

Jingchao Hu: hujingchao117@hotmail.com

Hua Wang: 18511712135@163.com

Zhipeng Fan: wang54384@163.com

Chunmei Zhang: 929814026@qq.com

Jingsong Wang: wjs99330@163.com

Chu-Tse Wu: wuct@nic.bmi.ac.cn

Songlin Wang: slwang@ccmu.edu.cn

Journal

Journal ID (nlm-ta): Stem Cell Res Ther

Journal ID (iso-abbrev): Stem Cell Res Ther

Title: Stem Cell Research & Therapy

Publisher: BioMed Central (London )

ISSN (Electronic): 1757-6512

Publication date (Electronic): 15 December 2015

Publication date PMC-release: 15 December 2015

Publication date Collection: 2015

Volume: 6

Electronic Location Identifier: 249

Affiliations

[ ]Molecular Laboratory for Gene Therapy & Tooth Regeneration, Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, Capital Medical University School of Stomatology, Tian Tan Xi Li No. 4, Beijing, 100050 P.R. China

[ ]Department of Stomatology, Beijing Jishuitan Hospital, No.31, Xinjiekou East Street, Xicheng District, Beijing, 100035 P.R. China

[ ]Department of Experimental Hematology, Beijing Institute of Radiation Medicine, 27 Taiping Road, Beijing, 100850 P.R. China

[ ]Department of Biochemistry and Molecular Biology, Capital Medical University School of Basic Medical Sciences, No.10 You An Men Wai Tou Tiao,, Beijing, 100069 P.R. China

Article

Publisher ID: 244

DOI: 10.1186/s13287-015-0244-5

PMC ID: 4681125

PubMed ID: 26670567

SO-VID: 3ecb3744-f3ab-4130-8f75-5f8c507e4d88

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 12 August 2015

Date revision received : 17 September 2015

Date accepted : 23 November 2015

Funding

Funded by: Beijing Municipality Government (Beijing Municipality Government grants)

Award ID: Beijing Scholar Program-PXM2013_014226_000055, PXM2015_014226_000116, PXM2015_014226_000055, PXM2015_014226_000052, PXM2014_014226_000048, PXM2014_014226_000013, PXM2014_014226_000053, Z121100005212004, PXM 2013_014226_000021, PXM 2013_014226_07_000080 and TJSHG201310025005

Award Recipient : Songlin Wang

Funded by: National Basic Research Program of China

Award ID: 2007CB947304 and 2010CB944801

Award Recipient : Songlin Wang

Funded by: FundRef http://dx.doi.org/10.13039/501100001809, National Natural Science Foundation of China (CN);

Award ID: 81371108

Award Recipient : Songlin Wang

Custom metadata

ScienceOpen disciplines: Molecular medicine

Keywords: dental pulp stem cells,cell injection,cell sheet,hepatocyte growth factor,periodontal regeneration

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ScienceOpen disciplines: Molecular medicine

Keywords: dental pulp stem cells, cell injection, cell sheet, hepatocyte growth factor, periodontal regeneration

Adenovirus-mediated transfer of hepatocyte growth factor gene to human dental pulp stem cells under good manufacturing practice improves their potential for periodontal regeneration in swine

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Abstract

Introduction

Method

Results

Conclusion

Electronic supplementary material

Related collections

Bacterial extracellular vesicles

Most cited references 25

Hepatocyte growth factor is a potent angiogenic factor which stimulates endothelial cell motility and growth

Mesenchymal stem cell implantation in a swine myocardial infarct model: engraftment and functional effects.

Cardiac stem cells possess growth factor-receptor systems that after activation regenerate the infarcted myocardium, improving ventricular function and long-term survival.

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