The study of the molecular targets and intervention strategies of human aging based on the human stem cell models
Worldwide population aging is unprecedented, pervasive and enduring, with implications for many facets of human life. China’s population is also aging and shrinking. By 2040, there will be about only 1.6 workers to 1 retiree in China, and the number of Chinese older than 65 is expected to rise from roughly 130 million to more than 320 million in 2050. The consequence for China’s demographic change is profound and challenging. Meanwhile, life expectancy around the world has increased steadily. Though people are living longer, they’re also increasingly battling chronic illnesses like osteoarthritis, diabetes, heart and neurodegenerative diseases. Therefore, the health of the aging population is the most important issue to combat. If people can experience these extra years of life in good health, their ability to do the things they value will be little different from that of a younger person.
Our research group is focusing on exploring the molecular targets and intervention strategies of human aging based on the human stem cell models. We established an efficient gene engineering approach to genetically correct mutated gene(s) in patient-specific iPSCs, and evaluate the mutation load attributable to genome editing technologies at single base pair level by Whole Genome Sequencing ( Cell Stem Cell 2011, 2014 ). Using a novel TTALE imaging system we developed in our lab, we can visualize the 3D dynamics of specific genomic structures under diverse physiological and pathological contexts across a wide range of cell types in vitro and in vivo ( Cell Research 2017 ). We established the platform for multiple human diseases studies and drug discovery (including Fanconi Anemia, Parkinson’s diseases, Premature aging, and Artherosclerosis etc.) by a combination of human induced pluripotent stem cell and genome editing technologies ( Nature 2012; Nature Communication, 2014; Nature Communication 2015; Cell 2016 ). Using the platform, we studied the underlying mechanisms of human aging, including unveiling the role of WRN in maintaining heterochromatin stability and highlight heterochromatin disorganization as a potential determinant of human aging ( Science 2015 ), and demonstrate the NRF2 pathway is a novel target for preventing aging-associated stem cell attrition to treat premature aging ( Cell 2016; Cell Research 2016 ). Moreover, we generated human stem cells via targeted genome editing harbouring more robust regenerative capacity and minimized risk of tumorigenesis over normal stem cells; which provides the first proof-of-concept of genetic enhancement of human stem cells, a strategy that may hold tremendous potential towards providing superior and safer stem cell replacement therapy. (Cell Research 2017).
We have screened and found several geroprotective compounds including Vitamin C (Nature-2012, Nature Communication-2014, 2015, Science-2015, Protein & Cell-2016, Cell-2016). Among the candidate compounds, we selected the most potential one for further evaluation in model organism, including mice and also non-human primates. Systematic studies of the Cynomolgus Monkeys’ specific tissues will be performed with or without anti-aging medication. The purpose of the study is to discover the potential therapeutic intervention for human aging and further elucidate its molecular mechanism.
Related Publications:
1.Wu Z, Zhang W, Song M, Wang W, Wei G, Li W, Lei J, Huang Y, Sang Y, Chan P, Chen C, Qu J*, Suzuki K*, Belmonte JC*, Liu GH*.(*Corresponding author) Differential stem cell aging kinetics in Hutchinson–Gilford progeria syndrome and Werner syndrome. Protein Cell. 2018. in press
Y2.ang J, Li J, Suzuki K, Liu X, Wu J, Zhang W, Ren R, Zhang W, Chan P, Izpisua Belmonte JC, Qu J*, Tang F*, Liu GH*. (*Corresponding author) Genetic enhancement in cultured human adult stem cells conferred by a single nucleotide recoding. Cell Res. 2017 Jul 7. doi: 10.1038/cr.2017.86.
Ren R, Deng L, Xue Y, Suzuki K, Zhang W, Yu Y, Wu J, Sun L, Gong X, Luan H, Yang F, Ju Z, Ren X, Wang S, Tang 3.H, Geng L, Zhang W, Li J, Qiao J, Xu T*, Qu J*, Liu GH*. (*Corresponding author) Visualization of aging-associated chromatin alterations with an engineered TALE system. Cell Res. 2017. Jan 31. doi: 10.1038/cr.2017.18.
4.Kubben N, Zhang W#, Wang L, Voss T, Yang J, Qu J#, Liu GH*, Misteli T* (#Co-senior author) Repression of the antioxidant NRF2 pathway in premature aging. Cell. 2016. 165,1-14. Highlighted by Cell (DOI: http://dx.doi.org/10.1016/j.cell.2016.05.061)
5.Suzuki K, Tsunekawa Y, Hernandez-Benitez R, Wu J, Zhu J, Kim EJ, Hatanaka F1, Yamamoto M, Araoka T, LiZ, Kurita M, Hishida T, Li M, Aizawa E, Guo S, Chen S, Goebl A, Soligalla RD, Qu J, Jiang T, Fu X, Jafari M, Esteban CR, Berggren WT, Lajara J, Nu？ez-Delicado E, Guillen P, Campistol JM, Matsuzaki F, Liu GH, Magistretti P, Zhang K, Callaway EM, Zhang K, Belmonte JC. In vivo genome editing via CRISPR/Cas9 mediated homology-independent targeted integration. Nature. 2016. 540(7631):144-149.
6.Fu L, XX, Ren R, Wu J, Zhang W, Yang J, Ren X, Wang S, Zhao Y, Sun L, Yu Y, Wang Z, Yang Z, Yuan Y, Qiao J, Belmonte JC*, Qu J*, Liu GH*. (*Corresponding author) Modeling Xeroderma Pigmentosum associated neurological pathologies with patients-derived iPSCs. Protein Cell. 2016. 7(3):210-21.
7.Li Y, Zhang W, Chang L, Han Y, Sun L, Guo X, Tang H, Liu Z, Deng H, Ye Y, Ren R, Wang Y, Li J, Qiao J, Qu J*, Zhang W*, Liu GH*. Vitamin C alleviates aging defects in a stem cell model for Werner syndrome. Protein Cell. 2016. Jun 6. (*Corresponding author)
8.Pan H, Guan D, Liu X, Li J, Wang L, Wu J, Zhou J, Zhang W, Ren R, Zhang W, Li Y, Yang J, Hao Y, Yuan T, Yuan G, Wang H, Ju Z, Mao Z, Li J, Qu J*, Tang F*, Liu GH*. (*Corresponding author) SIRT6 safeguards human mesenchymal stem cells from oxidative stress by coactivating NRF2. Cell Res. 2016 Jan 15. doi: 10.1038/cr.2016.4.
9.Duan S, Yuan G, Liu X, Ren R, Li J, Zhang W, Wu J, Xu X, Fu L, Li Y, Yang J, Zhang W, Bai R, Yi F, Suzuki K, Gao H, Esteban CR, Zhang C, Belmonte JC, Chen Z, Wang X, Jiang T, Qu J*, Tang F*, Liu GH*.(*Corresponding author) PTEN deficiency reprograms human neuralstem cells towards a glioblastoma stem cell-like phenotype. Nat Commun. 2015. 2015 Dec 3;6:10068. doi: 10.1038/ncomms10068.
10.Zhang W1, Li J1, Suzuki K1, Qu J1, Wang P, Zhou J, Liu X, Ren R, Xu X, Ocampo A, Yuan T, Yang J, Li Y, Shi L, Guan D, Pan H, Duan S, Ding Z, Li M, Yi F, Bai R, Wang Y, Chen C, Yang F, Li X, Wang Z, Aizawa E, Goebl A, Soligalla RD, Reddy P, Esteban CR, Tang F, Liu GH, Belmonte JC. (1equal contribution) A Werner syndrome stem cell model unveils heterochromatin alterations as a driver of human aging. Science. 2015 Apr 30. pii: aaa1356.
11.Suzuki K1, Yu C1, Qu J1, Li M1, Yao X, Yuan T, Goebl A, Tang S, Ren R, Aizawa E, Zhang F, Xu X, Soligalla R, Chen F, Kim J, Kim NY, Liao HK, Benner C, Esteban CR, Jin Y, Liu GH*, Li Y* , Belmonte JC*. (1equal contribution) Targeted gene correction in human disease-specific induced pluripotent stem cells minimally impacts whole-genome mutational load. Cell Stem Cell. 2014. 2014; 15, 31–36.
12.Liu GH1, Suzuki K1, Li M1, Qu J1, Montserrat N, Tarantino C, Gu Y, Yi F, Xu X, Zhang W, Ruiz S, Plongthongkum N, Zhang K, Masuda S, Nivet E, Tsunekawa Y, Soligalla R, Goebl A, Aizawa E, Kim N, Kim J, Dubova I, Li Y, Ren R, Benner C, del Sol A, Bueren J, Trujillo J, Surralles J, Esteban C, Izpisua Belmonte JC. (1equal contribution) Modeling Fanconi Anemia pathogenesis and therapeutics using integration-free patient-derived iPSCs. Nat Commun. 2014. DOI: 10.1038/ncomms5330.
13.Liu GH1, Qu J1, Suzuki K1, Nivet E, Li M, Montserrat N, Yi F, Xu X, Ruiz S, Zhang W, Ren B, Wagner U, Kim A, Li Y, Goebl A, Kim J, Soligalla R, Dubova I, Thompson J, Yates JIII, Esteban C, Sancho-Martinez I, Belmonte JC. (1equal contribution) Progressive degeneration of human neural stem cells caused by pathogenic LRRK2. Nature, 2012,491(7425):603-7. Highlighted by Nature Reviews Neurology (Nature Reviews Neurology | doi:10.1038/nrneurol.2012.230)
14.Liu GH, Yi F, Suzuki K, Qu J, Belmonte JC. Induced neural stem cells: a new tool for studying neural development and neurological disorders. Cell Res. 2012. 22(7):1087-91.
15.Liu GH1, Suzuki K1, Qu J1, Sancho-Martinez I, Yi F, Li M, Kumar S, Nivet E, Kim J, Soligalla RD, Dubova I, Goebl A, Plongthongkum N, Fung HL, Zhang K, Loring J, Laurent L, and Belmonte JC. (1equal contribution). Targeted gene correction of laminopathy-associated LMNA mutations in patient-specific iPSCs. Cell Stem Cell. 2011, 8(6):688-94. Highlighted by Nature (Nature 474, 8. doi:10.1038/474008c) and Cell Stem Cell (Cell Stem Cell 9, 2: 93-94)
16.Qu J1, Nakamura T1, Cao G, Mckercher S, Lipton S. (1equal contribution) S-Nitrosylation Activates Cdk5 and Contributes to Synaptic Spine Loss Induced by β-Amyloid Peptide. Proceedings of the National Academy of Sciences. 2011, 108(34):14330-5.
17.Liu GH, Barkho BZ, Ruiz S, Diep D, Qu J, Yang SL, Panopoulos AD, Suzuki K, Kurian L, Walsh C, Thompson J, Boue S, Fung HL, Sancho-Martinez I, Zhang K, Iii JY, Belmonte JC. Recapitulation of premature ageing with iPSCs from Hutchinson-Gilford progeria syndrome. Nature. 2011; 14;472: 221-5
18.Li M, Suzuki K, Qu J, Saini P, Dubova I, Yi F, Lee J, Sancho-Martinez I, Liu GH, Belmonte JC. Efficient correction of hemoglobinopathy-causing mutations by homologous recombination in integration-free patient iPSCs. Cell Res. 2011. 21(12):1740-4. Media coverage (www.youtube.com/watch?v=nEilyrzc9pY)