Experimental Regenerative Medicine: Stem Cell-derived Ganglion Cell Replacement Therapy in Glaucoma Models
Glaucoma is the second leading cause of blindness worldwide. It is an insidious and blinding disease, ultimately resulting in optic atrophy and loss of vision. Its etiology is complex and caused by genetic and environmental factors. Usually, irreversible retinal damage has already occurred when patients are diagnosed. Once detected, the progress of the disease can be slowed down by medicine. Nonetheless, later stages of glaucoma characteristically involve retinal and optic nerve damage. Thus, the development of regenerative medicine, i.e. cell replacement for glaucoma is of utmost clinical relevance.
In our laboratory, we have previously constructed a retinal/optic nerve organoid model in-a- dish for glaucoma. This stem cell derived in vitro glaucoma model shows different outgrowth of retinal ganglion cells compared to healthy controls. In the past, we have also used a glaucoma small animal model for treatment testing.
The focus of this PhD project is on in vitro cell replacement studies in glaucoma, which may be translated to in vivo studies in the second part of the project. Initially, the in vitro glaucoma model will be characterized further, using a number of biological read-outs including advanced microscopy, DNA and RNAseq, protein analysis, immunohistochemistry, ganglion cell subtype analysis, ganglion cell outgrowth assays, cellular imaging, bioinformatics and electrophysiology. Next, we aim to replace affected cells in the developing retinal/optic nerve organoid model with heathy (tagged) stem cells, in various ways and timepoints, and monitor potential success of the replacement in vitro. If successful, we aim to translate these finding to the in vivo situation. We expect that we can partly restore cellular damage or vision in vivo.
What can you expect?
The successful candidate will be gain expertise in molecular and cellular neurodegeneration and regeneration of the retina and optic nerve. The candidate will be trained in advanced molecular and cellular approaches based on human in vitro modelling of human retinal and optic nerve (glaucomatous) organoids and, where essential, with animal models. In addition, the candidate will benefit from the training activities scheduled by the EGRET-AAA program (workshops, meetings, …). After successful completion of the PhD, the trainee will obtain a joint doctorate of Amsterdam University and the Sorbonne University, Paris.
This project is a joint-doctorate between the Amsterdam UMC and the Vision Institute (Sorbonne University, Paris). At AUMC, the trainee will be daily supervised by Dr. Philip Wagstaff at the Bergen Ophthalmogenetics lab (https://ophthalmogenetics.nl). For direct clinical and pathological glaucoma issues, Dr. Sarah Janssen (Ophthalmology department AUMC) is involved. The AUMC offers all knowledge and facilities needed for this project. The trainee can participate in the world-leading Neuroscience School Amsterdam, and will conduct a short secondment project in the Nicol lab (Paris, Sorbonne UNI), to learn ins and outs of neural outgrowth of retinal explants. For the in vivo work, we partly rely on collaboration with Prof dr Bernstein, University of Bethesda, USA.
Who are we looking for?
We are looking for a highly motivated, dynamic and talented student who enjoys teamwork and has strong communication and interpersonal skills. The successful candidate must preferentially hold a laboratory based Neuroscience, Vision research or Molecular cell Biology Master obtained in the 2022-2023 academic year. Fluency in English is mandatory.
- The vast complexity of primary open angle glaucoma: disease genes, risks, molecular mechanisms and pathobiology. Janssen SF, Gorgels TG, Ramdas WD, Klaver CC, van Duijn CM, Jansonius NM, Bergen AA. Prog Retin Eye Res. 2013 Nov;37:31-67.
PMID: 24055863. https://pubmed.ncbi.nlm.nih.gov/24055863/
- An alternative approach to produce versatile retinal organoids with accelerated ganglion cell development. Wagstaff PE, Ten Asbroek ALMA, Ten Brink JB, Jansonius NM, Bergen AAB.
Sci Rep. 2021 Jan 13;11(1):1101. PMID: 33441707 https://pubmed.ncbi.nlm.nih.gov/33441707/
- The Role of Small Molecules and Their Effect on the Molecular Mechanisms of Early Retinal Organoid Development. Wagstaff PE, Heredero Berzal A, Boon CJF, Quinn PMJ, Ten Asbroek ALMA, Bergen AA. Int J Mol Sci. 2021 Jun 30;22(13):7081. PMID: 34209272.