Using human induced pluripotent stem cells to model brain and ageing diseases, to perform functional genomics and develop novel regenerative medicine approaches

Induced pluripotent stem cells and direct reprogrammed cell types capture an individual’s genetic make-up and constitute attractive and versatile model systems for performing human functional genomics. We combine reprogramming, CRISPR-Cas9 assisted genome/ epigenome modification and 2D and 3D (organoid) culture approaches with advanced imaging (optogenetics) and genome interrogation platforms (single cell RNA seq) to understand the molecular processes underlying human brain diseases and ageing with the aim of designing personalized precision medicine approaches.

Professor Ernst Wolvetang obtained his PhD from the University of Amsterdam, continued his post-doctoral training at the Monash Institute for Reproduction and Development, before joining the Australian Stem Cell Centre. In 2008 he was recruited to the AIBN where he heads the Stem Cell Engineering Laboratory and co-directs the UQ Centre in Stem Cell Ageing and Regenerative Engineering. He is a leader in the derivation, genome editing and disease modelling with human induced pluripotent stem cells, is the inaugural director of “Cell Reprogramming Australia”, and is a principal investigator in the ARC Centre of Excellence “Stem Cells Australia”. He was awarded the 2014 LSQ regenerative medicine prize. Professor Wolvetang serves on the editorial board of six stem cell journals; is listed inventor on four patents in stem cell research and he serves as a scientific advisor to the Massimo Foundation.

Collaborations

Professor Wolvetang collaborates with leading clinical researchers of neurological diseases such as Prof Marjo van der Knaap (VU Amsterdam) and Dr Adeline Vanderver (Washington Children Hospital) as well as with leaders in the cell reprogramming and stem cell field such as Dr Miguel Esteban (Guangzhou Institutes of Biomedicine and Health) and Professor Martin Pera (Jackson laboratories Bar Harbor, ME USA). Professor Wolvetang engages with the company InterK on testing peptide therapeutics and with the Massimo Foundation, BrAshAT and the GLIA consortium on finding and testing novel therapeutics for hypo-myelination diseases and childhood ataxias. The UQ Centre in stem cell ageing and Regenerative Engineering established in July 2016, co-directed by Professor Wolvetang, aims to develop novel therapeutic approaches to overcome the decline of stem cells with age.

Read More

Funding

Professor Wolvetang is the recipient of more than $3.5 million in grant funding in the past five years.

  • 2018-2021      Perry Cross Spinal Research Foundation CIA Ruitenberg, CIB Wolvetang, $400,000.
  • 2018–2020     CIA- Associate Professor Ernst Wolvetang, CIB Associate Professor Jessica Mar. Defective repair of neuronal activity-induced DNA double strand breaks: A novel pathogenic mechanism for neurodegeneration in ataxia-telangiectasia. NHMRC, $ 578,812
  • 2018-2021     CIA Prof. Geoff Faulkner, CIB Associate Professor Ernst Wolvetang.  Does L1 retrotransposition accentuate schizophrenia susceptibility and progression? NHMRC APP1138795, $725,585.
  • 2018                Prof. J. Cooper-White, Prof. Ernst Wolvetang, Dr Jana Vukovic, Dr Rodrigo Medeiros. ARC Linkage Infrastructure, Equipment and Facilities: ARC LIEF LE180100200. AutoStem: A high performance, automated stem cell bioengineering facility, $318,000.
  • 2017-2020      CIA Tam, CIB Wolvetang, CIC Cooper-White, CID  Ovchinnikov   Re-wiring a stem cell: Deciphering the molecular mechanism underpinning lineage propensity, NHMRC APP1127976, $ 855,780.
  • 2017-2021    CIA Lister, CIB Polo, CIC Wolvetang, CID Heng Leveraging genomics strategies to generate adult neurons from iPSCs and somatic cells, NHMRC APP1130168, $ 1,593,336.      
  • 2014-2017       CIA-Professor Ryan Lister, CIB- Associate Professor Ernst Wolvetang, CIC-Dr Oz Bogdanovic. Deciphering the role of atypical DNA methylation in neural genome regulation and neurological disorders, APP1090116, $751,116.
  • 2016-2016       Elucidating Asp-tRNA synthetase deficiency.  Massimo Foundation $50k 
  • 2014-2017       CIA- Associate Professor Ernst Wolvetang. Targeting cerebellar degeneration in Ataxia-Telangiectasia using induced pluripotent stem cells. BrAshat grant $375,400.
  • 2014-2016       CIA- Associate Professor Ernst Wolvetang CIB- Associate Professor Christine Wells. Understanding Alzheimer's disease using Down syndrome as a model. University of Queensland NHMRC APP1062802 $756,894.      
  • 2013-2015       CIA - Professor Melissa Little CIB - Associate Professor Ernst Wolvetang CIC - Professor Justin Cooper-White. Directed differentiation of human embryonic stem cells to kidney progenitors. University of Queensland. NHMRC APP1041277. $ 630.158.
  • 2013-2016       CIA - Associate Professor Ernst Wolvetang CIB -Doctor Ryan Taft CIC - Professor Merlin Butler. Investigation of processed snoRNAs as cryptic regulators of the imprinted Prader-Willi syndrome locus.  University of Queensland. NHMRC APP1043023.  $ 650,802
  • 2011-2018       22 Investigators including Wolvetang E
    ARC Special Research Initiative in Stem Cell Science, Stem Cells Australia. (University of Melbourne,  Monash University, University of Queensland, University of New South Wales, Walter and Eliza Hall Institute & CSIRO). $21 million
  • 2012-2015       Lavin M , Wolvetang E
    Reprogramming of Ataxia-Telangiectaxia fibroblasts to generate iPS cells University of Queensland. NHMRC APP1021005 $ 581,010.00

Media:

Key Publications

  1. Andrii Slonchak, Xiaohui Wang, Harman Chaggar, Julio Aguado, Morgan Freney, Kexin Yan, Francisco J Torres, Alberto A Amarilla, Rickyle Balea, Julian D. J. Sng, Yin Xiang Setoh, Nias Peng, Daniel Watterson, Andreas Suhrbier,  Ernst Wolvetang*, Alexander A Khromykh*. Zika virus noncoding RNA cooperates with the viral protein NS5 to inhibit STAT1 phosphorylation and facilitate viral pathogenesis. Science adv. (2022) in press.
  2. Aguado, Julio, Fabrizio d’Adda di Fagagna, and Ernst Wolvetang. "Telomere transcription in ageing." Ageing Research Reviews 62 (2020): 101115.
  3. Aguado, Julio, et al. "Inhibition of the cGAS‐STING pathway ameliorates the premature senescence hallmarks of Ataxia‐Telangiectasia brain organoids." Aging Cell 20.9 (2021): e13468.
  4. Aguado, J., Gómez-Inclán, C., Leeson, H. C., Lavin, M. F., Shiloh, Y., & Wolvetang, E. J. (2022). The Hallmarks of Aging in Ataxia-Telangiectasia. Ageing Research Reviews, 101653.
  5. Shaker MR, Aguado J, Chaggar HK, Wolvetang EJ. Klotho inhibits neuronal senescence in human brain organoids. npj Aging and Mechanisms of Disease. 2021 Aug 2;7(1):1-2.
  6. Setoh, Yin Xiang, et al. "Determinants of Zika virus host tropism uncovered by deep mutational scanning." Nature microbiology 4.5 (2019): 876-887.
  7. Shaker, Mohammed R., et al. "Rapid and efficient generation of myelinating human oligodendrocytes in organoids." Frontiers in cellular neuroscience 15 (2021): 631548.
  8. Ovchinnikov DA, Korn O, Virshup I, Wells CA, Wolvetang EJ. The impact of APP on Alzheimer-like pathogenesis and gene expression in down syndrome iPSC-derived neurons. Stem cell reports. 2018 Jul 10;11(1):32-42.
  9. Shaker MR, Kahtan A, Prasad R, Lee JH, Pietrogrande G, Leeson HC, Sun W, Wolvetang EJ, Slonchak A. Neural epidermal growth factor-like like protein 2 Is expressed in human oligodendroglial cell types. Frontiers in Cell and Developmental Biology. 2022;10.
  10. Leeson HC, Goh D, Coman D, Wolvetang EJ. Generation of iPSC lines from hereditary spastic paraplegia 56 (SPG56) patients and family members carrying CYP2U1 mutations. Stem Cell Research. 2022 Sep 14:102917.
  11. Wolvetang E, Herszfeld D, Langton-Bunker E, Chung T, Filipczyk A, Houssami S, Koh K, Laslett AL, Michalska A, Nguyen L, Reubinoff BE, Tellis I, Auerbach JM, Ording CJ, Looijenga LHJ, Pera MF. (2006) CD30 is a survival factor and a biomarker for transformed human pluripotent stem cells. Nat Biotech 24(3), 351-357.
  12. Nayler SP, Gatei M, Kozlov S, Gatti R, Mar JC, Wells CA, Lavin M, Wolvetang EJ. (2012) Induced pluripotent stem cells from ataxia-telangiectasia recapitulate the cellular phenotype. Stem cells Translational Medicine 1, 523-535
  13. Chung T-L, Brena RM, Kolle G, Grimmond SM, Berman BP, Laird PW, Pera MF, Wolvetang EJ. (2010) Vitamin C promotes widespread yet specific demethylation of the hESC epigenome. Stem Cells 28(10), 1848-1855.
  14. Minoru Takasato, Pei X Er, Han Chiu, Barbara Maier, Gregory J Baillie, Charles Ferguson, Robert G Parton, Ernst Wolvetang, Mathias S Roost, Susana M Chuva de Sousa Lopes, Melissa H Little Kidney organoids from human iPS cells contain multiple cell types and model human nephrogenesis (2015) Nature 526, 564–568.
  15. Sabine Klawitter, Nina V. Fuchs, Kyle R. Upton, Martin Muñoz-Lopez4, Ruchi Shukla, Jichang Wang, Marta Garcia-Canadas, Daniel J. Gerhardt, Johannes Löwer, Ivana Grabundzija, Attila Sebe, Balázs Sarkadi, Sylvia Merkert, Anett Witthuhn, Alexandra Haase, Ernst J. Wolvetang, Ulrich Martin, Zoltán Ivics, Zsuzsanna Izsvák, Jose L. Garcia-Perez, Geoffrey J. Faulkner and Gerald G. Schumann. Reprogramming triggers endogenous L1, Alu and SVA retrotransposition in human induced pluripotent stem cells. (2016) Nature Comm 7.
  16. Olivier J. Becherel, Jane Sun,  Abrey J. Yeo, Sam Nayler, Brent  L. Fogel, Fuying Gao, Giovanni Coppola, Chiara Criscuolo, Giuseppe De Michele, Martin F. Lavin*and Ernst Wolvetang*. A new model to study neurodegeneration in Ataxia Oculomotor Apraxia Type 2. Hum.Mol Gen.  (2015) ddv296
  17. Briggs JA, Sun J, Shepherd J, Ovchinnikov DA, Chung TL, Nayler SP, Kao LP, Morrow CA, Thakar NY, Soo SY, Peura T, Grimmond SM, Wolvetang EJ. (2012) Integration-free iPS cells identify genetic and neural developmental features of Down syndrome etiology. Stem Cells 31(3), 467-478.
Featured projects Duration
MRFF Clinical Trials - Rare Cancers, Rare Diseases and Unmet Need Grant. Ataxia-telangiectasia: treating mitochondrial dysfunction with a novel form of anaplerosis
20202023
ATM at the crossroads of DNA damage, ageing and cerebellar degeneration
20172019
Mechano-driven changes to cardiac tissue function during ageing
20192021
ARC DP Mimicking the perivascular niche with boronolectin-based biomaterials
20192023
Brain organoids for modeling human neuropathogensis
20172019
Implication of the microglia in adult neurogenesis process
20172019
NSCFA/BrAsh-AT: Using derived liver organoids to test the efficacy of an existing therapeutic (CAT-SKL) to overcome or improve liver dysfunction in children with Ataxia Telangiectasia
Is Down syndrome a neurocristopathy?
20172019
Personalising Epilepsy Regimes with Stem cells and artificial Intelligence models for Superior Treatment outcomes (PERSIST)
20212024
Elucidating the genetic drivers of accelerated cellular ageing in Down syndrome
Unravelling the molecular basis of novel leukodystrophies
20172019
NHMRC-MRFF AR LEUKODYSTROPHIES FLAGSHIP “The Massimo Mission”
NMSS Modulating microglial activity for treatment of demyelinating diseases of the CNS
Probing molecular determinants of Ageing using human IPSC and reprogramming models
20172019
Deciphering disease heterogeneity: Spatiotemporal analysis of molecular and cellular pathology in HBSL
Epigenetic and functional maturation of iPSC derived neuronal cells
20172019
ARC DP: Safer gene editing tools for Australian livestock and biotech industries
Developing a microfluidic and 3D bioprinting platforms to model and study the human perivascular niche
20162019
Genetic Cure 4 kids: Hereditary Spastic Paraplegia Research Model
Developing novel materials to direct stem cell behaviour and tissue rejuvenation
20162019
NHMRC 2020 Stem Cell Therapies Mission
20212024
Down syndrome as an Ageing model
20172019
NHMRC 2020 MRFF Childhood Cancer Research: ABOLISH Neuroblastoma: Defining the Aetiology and underlying BiOLogy of neuroblastoma to Innovate and SHape new options for prevention, diagnosis and treatment
20212024
Genetic and epigenetic manipulations of neural stem cells and ageing
20172019
NHMRC- MRFF 2020 Genomics Health Futures Mission. The Australian Functional Genomics Network
20212026
Ageing of the human haemopoietic stem cell niche
20172019