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Prof. Dr. Philipp Koch

Stem Cell-based Models of Psychiatric Disorders

Psychiatric disorders are a heterogeneous group of mental illnesses associated with a high social and economic burden on patients and society. The complex etiology of these disorders, coupled with our limited understanding of the structural and functional abnormalities affecting the brains of neuropsychiatric patients, has made it difficult to develop effective medical treatment strategies. At the Hector Institute for Translational Brain Research (HITBR) we aim at leveraging the recent advances in stem cell technologies to develop cell-based models of mental disorders.

We make use of cellular forward and backward programming of patient-derived somatic cells into induced pluripotent stem cells (iPSCs), neurons and glia in order to generate cellular in vitro models of psychiatric diseases (2D as well as cerebral organoids). By merging iPS cell technology with multi-OMICs phenotyping, we try to understand the molecular mechanisms involved in the physiopathology of mental illnesses and to explore new drug targets. As reprogrammed cells carry the genetic background of a patient, they represent a valid platform to identify genetic predictors of drug responses and to associate cellular abnormalities with clinical phenotypes in a human context.

National and international Joint Research Projects

  • Prevention of neuronal protein aggregation through endogenous mechanisms1 (EndoProtect, BMBF)
  • A systems-medicine approach towards distinct and shared resilience and pathological mechanisms of substance use disorders (SysMedSUD, BMBF)
  • Deciphering alcohol addiction-associated gene regulation changes on a single cell level (DFG)

Selected publications

  1. Asymmetric Notch activity by differential inheritance of lysosomes in human neural stem cells.
    Bohl B, Jabali A, Ladewig J, Koch P. Sci Adv. 2022. 8(6):eabl5792. doi: 10.1126/sciadv.abl5792.
  2. In Vitro Recapitulation of Developmental Transitions in Human Neural Stem Cells.
    Ostermann L, Ladewig J, Müller FJ, Kesavan J, Tailor J, Smith A, Brüstle O, Koch P.  Stem Cells. 2019. 37(11):1429-1440. doi: 10.1002/stem.3065.
  3. Analysis of short tandem repeat expansions and their methylation state with nanopore sequencing.
    Giesselmann P, Brändl B, Raimondeau E, Bowen R, Rohrandt C, Tandon R, Kretzmer H, Assum G, Galonska C, Siebert R, Ammerpohl O, Heron A, Schneider SA, Ladewig J, Koch P, Schuldt BM, Graham JE, Meissner A, Müller FJ.  Nat Biotechnol. 2019. 37(12):1478-1481. doi: 10.1038/s41587-019-0293-x.

  4. Genome Editing in Neuroepithelial Stem Cells to Generate Human Neurons with High Adenosine-Releasing Capacity
    Poppe D, Doerr J, Schneider M, Wilkens R, Steinbeck JA, Ladewig J, Tam A, Paschon DE, Gregory PD, Reik A, Müller CE, Koch P*, Brüstle O*. Stem Cells Transl Med. 2018. 7(6):477-486. doi: 10.1002/sctm.16-0272. *corresponding author
  5. An Organoid-Based Model of Cortical Development Identifies Non-Cell-Autonomous Defects in Wnt Signaling Contributing to Miller-Dieker Syndrome
    Iefremova V, Manikakis G, Krefft O, Jabali A, Weynans K, Wilkens R, Marsoner F, Brändl B, Müller FJ, Koch P*, Ladewig J*. Cell Rep. 2017. 19(1):50-59. doi: 10.1016/j.celrep.2017.03.047. *corresponding author
  6. Arylsulfatase A Overexpressing Human iPSC-derived Neural Cells Reduce CNS Sulfatide Storage in a Mouse Model of Metachromatic Leukodystrophy.
    Doerr J, Böckenhoff A, Ewald B, Ladewig J, Eckhardt M, Gieselmann V, Matzner U, Brüstle O, Koch P.  Mol Ther. 2015. 23(9):1519-31. doi: 10.1038/mt.2015.106.
  7. Auto-attraction of neural precursors and their neuronal progeny impairs neuronal migration.
    Ladewig J*, Koch P*, Brüstle O. Nat Neurosci. 2014. 17(1):24-6. doi: 10.1038/nn.3583. *shared first author 
  8. APP processing in human pluripotent stem cell-derived neurons is resistant to NSAID-based γ-secretase modulation.
    Mertens J, Stüber K, Wunderlich P, Ladewig J, Kesavan JC, Vandenberghe R, Vandenbulcke M, van Damme P, Walter J, Brüstle O, Koch P.  Stem Cell Reports. 2013. 1(6):491-8. doi: 10.1016/j.stemcr.2013.10.011. eCollection 2013.
  9. Small molecules enable highly efficient neuronal conversion of human fibroblasts.
    Ladewig J, Mertens J, Kesavan J, Doerr J, Poppe D, Glaue F, Herms S, Wernet P, Kögler G, Müller FJ, Koch P*, Brüstle O*. Nat Methods. 2012. 9(6):575-8. doi: 10.1038/nmeth.1972. *corresponding author 
  10. Excitation-induced ataxin-3 aggregation in neurons from patients with Machado-Joseph disease. Koch P, Breuer P, Peitz M, Jungverdorben J, Kesavan J, Poppe D, Doerr J, Ladewig J, Mertens J, Tüting T, Hoffmann P, Klockgether T, Evert BO, Wüllner U, Brüstle O.  Nature. 2011. 480(7378):543-6. doi: 10.1038/nature10671.

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