Therapeutic function of a novel rat induced pluripotent stem cell line in a 6‑OHDA‑induced rat model of Parkinson's disease

Xu,Jiajia; Li,Yangyang; Zhu,Huan; Wu,Wenyu; Liu,Yumeng; Guo,Yu; Guan,Weijun; Liu,Changqing; Ma,Caiyun

doi:10.3892/ijmm.2022.5196

Therapeutic function of a novel rat induced pluripotent stem cell line in a 6‑OHDA‑induced rat model of Parkinson's disease

Authors:
- Jiajia Xu
- Yangyang Li
- Huan Zhu
- Wenyu Wu
- Yumeng Liu
- Yu Guo
- Weijun Guan
- Changqing Liu
- Caiyun Ma
View Affiliations

Affiliations: School of Life Sciences, Bengbu Medical College, Bengbu, Anhui 233000, P.R. China, Department of Blood Transfusion, The Affiliated Hospital of Yangzhou University, Yangzhou, Jiangsu 225001, P.R. China, School of Laboratory Medicine, Bengbu Medical College, Bengbu, Anhui 233000, P.R. China, National Germplasm Resource Center for Domestic Animals, Institute of Beijing Animal and Veterinary Science, Chinese Academy of Agricultural Science, Beijing 100193, P.R. China
Published online on: October 26, 2022 https://doi.org/10.3892/ijmm.2022.5196
Article Number: 140
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

Parkinson's disease (PD) is a progressive neurodegenerative movement disorder of the central nervous system that results from the loss of dopaminergic (DA) nigral neurons. Induced pluripotent stem cells (iPSCs) have shown potential for cell transplantation treatment of neurodegenerative disorders. In the present study, the small molecules CHIR99021 and RepSox (CR) significantly facilitated reprogramming and enhanced the efficiency of GFP+/iPS‑like colonies [rat iPSCs induced by OCT3/4, Sox2, Klf4, c‑Myc, Nanog and Lin28 + CR (RiPSCs‑6F/CR)] generation by ~4.0‑fold during lentivirus‑mediated reprogramming of six transcription factors in rat embryonic fibroblasts. The generation of iPSCs was detected by reverse transcription‑PCR, immunofluorescence and western blot analysis. Subsequently, RiPSCs‑6F/CR were stereotactically transplanted into the right medial forebrain bundle (MFB) of 6‑hydroxydopamine‑lesioned rats with PD. The transplanted RiPSCs‑6F/CR survived and functioned in the MFB of rats with PD for ≥20 weeks, and significantly improved functional restoration from their PD‑related behavioral defects. Furthermore, the grafted RiPSCs‑6F/CR could migrate and differentiate into various neurocytes in vivo, including γ aminobutyric acid‑ergic, DA neurons and glial cells. In conclusion, the present study confirmed that RiPSCs‑6F/CR induced by small molecules could be used as potential donor material for neural grafting to remodel basal ganglia circuitry in neurodegenerative diseases.

View Figures

View References

1	Guo Y, Guan Y, Zhu H, Sun T, Wang Y, Huang Y, Ma C, Emery R, Guan W, Wang C and Liu C: Therapeutic function of iPSCs-derived primitive neuroepithelial cells in a rat model of Parkinson's disease. Neurochem Int. 155:1053242022. View Article : Google Scholar : PubMed/NCBI
2	Tang Y, Meng L, Wan CM, Liu ZH, Liao WH, Yan XX, Wang XY, Tang BS and Guo JF: Identifying the presence of Parkinson's disease using low-frequency fluctuations in BOLD signals. Neurosci Lett. 645:1–6. 2017. View Article : Google Scholar : PubMed/NCBI
3	Parmar M, Grealish S and Henchcliffe C: The future of stem cell therapies for Parkinson disease. Nat Rev Neurosci. 21:103–115. 2020. View Article : Google Scholar : PubMed/NCBI
4	Armstrong MJ and Okun MS: Diagnosis and treatment of Parkinson disease: A review. JAMA. 323:548–560. 2020. View Article : Google Scholar : PubMed/NCBI
5	Blesa J and Przedborski S: Parkinson's disease: Animal models and dopaminergic cell vulnerability. Front Neuroanat. 8:1552014. View Article : Google Scholar
6	Burke RE, Cadet JL, Kent JD, Karanas AL and Jackson-Lewis V: An assessment of the validity of densitometric measures of striatal tyrosine hydroxylase-positive fibers: Relationship to apomorphine-induced rotations in 6-hydroxydopamine lesioned rats. J Neurosci Methods. 35:63–73. 1990. View Article : Google Scholar : PubMed/NCBI
7	Bergman H, Wichmann T and DeLong MR: Reversal of experimental parkinsonism by lesions of the subthalamic nucleus. Science. 249:1436–1438. 1990. View Article : Google Scholar : PubMed/NCBI
8	Poewe W, Seppi K, Tanner CM, Halliday GM, Brundin P, Volkmann J, Schrag AE and Lang AE: Parkinson disease. Nat Rev Dis Primers. 3:170132017. View Article : Google Scholar : PubMed/NCBI
9	Limousin P and Foltynie T: Long-term outcomes of deep brain stimulation in Parkinson disease. Nat Rev Neurol. 15:234–242. 2019. View Article : Google Scholar : PubMed/NCBI
10	Hitti FL, Ramayya AG, McShane BJ, Yang AI, Vaughan KA and Baltuch GH: Long-term outcomes following deep brain stimulation for Parkinson's disease. J Neurosurg. Jan 18–2019.Epub ahead of print. PubMed/NCBI
11	Karl JA, Ouyang B, Colletta K and Verhagen Metman L: Long-term satisfaction and Patient-centered outcomes of deep brain stimulation in Parkinson's disease. Brain Sci. 8:602018. View Article : Google Scholar
12	Liu Z and Cheung HH: Stem cell-based therapies for Parkinson disease. Int J Mol Sci. 21:80602020. View Article : Google Scholar :
13	Pan T, Xu J and Zhu Y: Self-renewal molecular mechanisms of colorectal cancer stem cells. Int J Mol Med. 39:9–20. 2017. View Article : Google Scholar
14	Takahashi K, Tanabe K, Ohnuki M, Narita M, Ichisaka T, Tomoda K and Yamanaka S: Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell. 131:861–872. 2007. View Article : Google Scholar : PubMed/NCBI
15	Aoi T: 10th anniversary of iPS cells: The challenges that lie ahead. J Biochem. 160:121–129. 2016. View Article : Google Scholar : PubMed/NCBI
16	Sonntag KC, Song B, Lee N, Jung JH, Cha Y, Leblanc P, Neff C, Kong SW, Carter BS, Schweitzer J and Kim KS: Pluripotent stem cell-based therapy for Parkinson's disease: Current status and future prospects. Prog Neurobiol. 168:1–20. 2018. View Article : Google Scholar : PubMed/NCBI
17	de Lau LM and Breteler MM: Epidemiology of Parkinson's disease. Lancet Neurol. 5:525–535. 2006. View Article : Google Scholar : PubMed/NCBI
18	Takahashi K and Yamanaka S: Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell. 126:663–676. 2006. View Article : Google Scholar : PubMed/NCBI
19	Yu J, Vodyanik MA, Smuga-Otto K, Antosiewicz-Bourget J, Frane JL, Tian S, Nie J, Jonsdottir GA, Ruotti V, Stewart R, et al: Induced pluripotent stem cell lines derived from human somatic cells. Science. 318:1917–1920. 2007. View Article : Google Scholar : PubMed/NCBI
20	Chhabra A: Inherent immunogenicity or lack thereof of pluripotent stem cells: Implications for cell replacement therapy. Front Immunol. 8:9932017. View Article : Google Scholar : PubMed/NCBI
21	Tiscornia G, Vivas EL and Izpisua Belmonte JC: Diseases in a dish: Modeling human genetic disorders using induced pluripotent cells. Nat Med. 17:1570–1576. 2011. View Article : Google Scholar : PubMed/NCBI
22	Singh VK, Kalsan M, Kumar N, Saini A and Chandra R: Induced pluripotent stem cells: Applications in regenerative medicine, disease modeling, and drug discovery. Front Cell Dev Biol. 3:22015. View Article : Google Scholar : PubMed/NCBI
23	Brevini TA, Pennarossa G, Manzoni EF, Gandolfi CE, Zenobi A and Gandolfi F: The quest for an effective and safe personalized cell therapy using epigenetic tools. Clin Epigenetics. 8:1192016. View Article : Google Scholar : PubMed/NCBI
24	Kim J, Jeon J, Song B, Lee N, Ko S, Cha Y, Leblanc P, Seo H and Kim KS: Spotting-based differentiation of functional dopaminergic progenitors from human pluripotent stem cells. Nat Protoc. 17:890–909. 2022. View Article : Google Scholar : PubMed/NCBI
25	Samata B, Doi D, Nishimura K, Kikuchi T, Watanabe A, Sakamoto Y, Kakuta J, Ono Y and Takahashi J: Purification of functional human ES and iPSC-derived midbrain dopaminergic progenitors using LRTM1. Nat Commun. 7:130972016. View Article : Google Scholar : PubMed/NCBI
26	Song B, Cha Y, Ko S, Jeon J, Lee N, Seo H, Park KJ, Lee IH, Lopes C, Feitosa M, et al: Human autologous iPSC-derived dopaminergic progenitors restore motor function in Parkinson's disease models. J Clin Invest. 130:904–920. 2020. View Article : Google Scholar :
27	Kikuchi T, Morizane A, Doi D, Magotani H, Onoe H, Hayashi T, Mizuma H, Takara S, Takahashi R, Inoue H, et al: Human iPS cell-derived dopaminergic neurons function in a primate Parkinson's disease model. Nature. 548:592–596. 2017. View Article : Google Scholar : PubMed/NCBI
28	Hallett PJ, Deleidi M, Astradsson A, Smith GA, Cooper O, Osborn TM, Sundberg M, Moore MA, Perez-Torres E, Brownell AL, et al: Successful function of autologous iPSC-derived dopamine neurons following transplantation in a non-human primate model of Parkinson's disease. Cell Stem Cell. 16:269–274. 2015. View Article : Google Scholar : PubMed/NCBI
29	Guo Y, Zhu H, Li X, Ma C, Sun T, Wang Y, Wang C, Guan W and Liu C: Multiple functions of reversine on the biological characteristics of sheep fibroblasts. Sci Rep. 11:123652021. View Article : Google Scholar : PubMed/NCBI
30	Shenoy S: CDH1 (E-Cadherin) mutation and gastric cancer: Genetics, molecular mechanisms and guidelines for management. Cancer Manag Res. 11:10477–10486. 2019. View Article : Google Scholar : PubMed/NCBI
31	Li M, Wang J, Wang C, Xia L, Xu J, Xie X and Lu W: Microenvironment remodeled by tumor and stromal cells elevates fibroblast-derived COL1A1 and facilitates ovarian cancer metastasis. Exp Cell Res. 394:1121532020. View Article : Google Scholar : PubMed/NCBI
32	Foot O, Hallin M, Bague S, Jones RL and Thway K: Superficial CD34-positive fibroblastic tumor. Int J Surg Pathol. 28:879–881. 2020. View Article : Google Scholar : PubMed/NCBI
33	Zarei R, Nikpour P, Rashidi B, Eskandari N and Aboutorabi R: Evaluation of Muc1 Gene expression at the time of implantation in diabetic rat models treated with insulin, metformin and pioglitazone in the normal cycle and ovulation induction cycle. Int J Fertil Steril. 14:218–222. 2020.PubMed/NCBI
34	Vakhrusheva A, Endzhievskaya S, Zhuikov V, Nekrasova T, Parshina E, Ovsiannikova N, Popov V, Bagrov D, Minin AA and Sokolova OS: The role of vimentin in directional migration of rat fibroblasts. Cytoskeleton (Hoboken). 76:467–476. 2019. View Article : Google Scholar
35	Jia M, Qiu H, Lin L, Zhang S, Li D and Jin D: Inhibition of PI3K/AKT/mTOR signalling pathway activates autophagy and suppresses peritoneal fibrosis in the process of peritoneal dialysis. Front Physiol. 13:7784792022. View Article : Google Scholar : PubMed/NCBI
36	Guo Y, Zhu H, Li X, Ma C, Li Y, Sun T, Wang Y, Wang C, Guan W and Liu C: RepSox effectively promotes the induced differentiation of sheep fibroblasts into adipocytes via the inhibition of the TGFβ1/Smad pathway. Int J Mol Med. 48:1482021. View Article : Google Scholar
37	Yang Y, Wang QQ, Bozinov O, Xu RX, Sun YL and Wang SS: GSK3 inhibitor CHIR99021 enriches glioma stemlike cells. Oncol Rep. 43:1479–1490. 2020.PubMed/NCBI
38	Li X, Guo Y, Yao Y, Hua J, Ma Y, Liu C and Guan W: Reversine increases the plasticity of long-term cryopreserved fibroblasts to multipotent progenitor cells through activation of Oct4. Int J Biol Sci. 12:53–62. 2016. View Article : Google Scholar : PubMed/NCBI
39	Casarrubea M, Sorbera F and Crescimanno G: Structure of rat behavior in hole-board: II) multivariate analysis of modifications induced by diazepam. Physiol Behavior. 96:683–692. 2009. View Article : Google Scholar
40	Li X, Zuo X, Jing J, Ma Y, Wang J, Liu D, Zhu J, Du X, Xiong L, Du Y, et al: Small-molecule-driven direct reprogramming of mouse fibroblasts into functional neurons. Cell Stem Cell. 17:195–203. 2015. View Article : Google Scholar : PubMed/NCBI
41	Li Y, Zhang Q, Yin X, Yang W, Du Y, Hou P, Ge J, Liu C, Zhang W, Zhang X, et al: Generation of iPSCs from mouse fibroblasts with a single gene, Oct4, and small molecules. Cell Res. 21:196–204. 2011. View Article : Google Scholar
42	Cao N, Huang Y, Zheng J, Spencer CI, Zhang Y, Fu JD, Nie B, Xie M, Zhang M, Wang H, et al: Conversion of human fibroblasts into functional cardiomyocytes by small molecules. Science. 352:1216–1220. 2016. View Article : Google Scholar : PubMed/NCBI
43	Ma Y, Xie H, Du X, Wang L, Jin X, Zhang Q, Han Y, Sun S, Wang L, Li X, et al: In vivo chemical reprogramming of astrocytes into neurons. Cell Discov. 7:122021. View Article : Google Scholar : PubMed/NCBI
44	Cartwright P, McLean C, Sheppard A, Rivett D, Jones K and Dalton S: LIF/STAT3 controls ES cell self-renewal and pluripotency by a Myc-dependent mechanism. Development. 132:885–896. 2005. View Article : Google Scholar : PubMed/NCBI
45	Liao J, Cui C, Chen S, Ren J, Chen J, Gao Y, Li H, Jia N, Cheng L, Xiao H and Xiao L: Generation of induced pluripotent stem cell lines from adult rat cells. Cell Stem Cell. 4:11–15. 2009. View Article : Google Scholar
46	Hirabayashi M and Hochi S: Embryonic stem (ES) cells and induced pluripotent stem (iPS) cells in rats. Reprod Med Biol. 10:231–238. 2011. View Article : Google Scholar : PubMed/NCBI
47	Yasuda S, Kusakawa S, Kuroda T, Miura T, Tano K, Takada N, Matsuyama S, Matsuyama A, Nasu M, Umezawa A, et al: Tumorigenicity-associated characteristics of human iPS cell lines. PLoS One. 13:e02050222018. View Article : Google Scholar : PubMed/NCBI
48	Fong CY, Gauthaman K and Bongso A: Teratomas from pluripotent stem cells: A clinical hurdle. J Cell Biochem. 111:769–781. 2010. View Article : Google Scholar : PubMed/NCBI
49	Doi D, Morizane A, Kikuchi T, Onoe H, Hayashi T, Kawasaki T, Motono M, Sasai Y, Saiki H, Gomi M, et al: Prolonged maturation culture favors a reduction in the tumorigenicity and the dopaminergic function of human ESC-derived neural cells in a primate model of Parkinson's disease. Stem Cells. 30:935–945. 2012. View Article : Google Scholar : PubMed/NCBI
50	Wei ZD and Shetty AK: Treating Parkinson's disease by astrocyte reprogramming: Progress and challenges. Sci Adv. 7:eabg31982021. View Article : Google Scholar : PubMed/NCBI
51	Duan L, Bhattacharyya BJ, Belmadani A, Pan L, Miller RJ and Kessler JA: Stem cell derived basal forebrain cholinergic neurons from Alzheimer's disease patients are more susceptible to cell death. Mol Neurodegener. 9:32014. View Article : Google Scholar : PubMed/NCBI
52	Abdul Wahid SF, Law ZK, Ismail NA and Lai NM: Cell-based therapies for amyotrophic lateral sclerosis/motor neuron disease. Cochrane Database Syst Rev. 12:CD0117422019.PubMed/NCBI
53	Han F, Liu Y, Huang J, Zhang X and Wei C: Current approaches and molecular mechanisms for directly reprogramming fibroblasts into neurons and dopamine neurons. Front Aging Neurosci. 13:7385292021. View Article : Google Scholar : PubMed/NCBI
54	D'Souza GX, Rose SE, Knupp A, Nicholson DA, Keene CD and Young JE: The application of in vitro-derived human neurons in neurodegenerative disease modeling. J Neurosci Res. 99:124–140. 2021. View Article : Google Scholar
55	Ke M, Chong CM and Su H: Using induced pluripotent stem cells for modeling Parkinson's disease. World J Stem Cells. 11:634–649. 2019. View Article : Google Scholar : PubMed/NCBI
56	Schweitzer JS, Song B, Herrington TM, Park TY, Lee N, Ko S, Jeon J, Cha Y, Kim K, Li Q, et al: Personalized iPSC-derived dopamine progenitor cells for Parkinson's disease. N Engl J Med. 382:1926–1932. 2020. View Article : Google Scholar : PubMed/NCBI
57	Tang Y and Cheng L: Cocktail of chemical compounds robustly promoting cell reprogramming protects liver against acute injury. Protein Cell. 8:273–283. 2017. View Article : Google Scholar : PubMed/NCBI
58	Zhou Y, Zhu X, Dai Y, Xiong S, Wei C, Yu P, Tang Y, Wu L, Li J, Liu D, et al: Chemical cocktail induces hematopoietic reprogramming and expands hematopoietic stem/progenitor cells. Adv Sci (Weinh). 7:19017852020. View Article : Google Scholar
59	Lin X, Li AM, Li YH, Luo RC, Zou YJ, Liu YY, Liu C, Xie YY, Zuo S, Liu Z, et al: Silencing MYH9 blocks HBx-induced GSK3beta ubiquitination and degradation to inhibit tumor stemness in hepatocellular carcinoma. Signal Transduct Target Ther. 5:132020. View Article : Google Scholar
60	Guan J, Wang G, Wang J, Zhang Z, Fu Y, Cheng L, Meng G, Lyu Y, Zhu J, Li Y, et al: Chemical reprogramming of human somatic cells to pluripotent stem cells. Nature. 605:325–331. 2022. View Article : Google Scholar : PubMed/NCBI