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Retinal stem cell research and neurogenesis – Mike O. Karl

Picture: human retinal organoid – microscopic image of an immunostained histologic crossection. © Manuela Völkner /MOKALAB CRTD

The MOKALAB investigates mechanisms of neurodegeneration in the human retina, and its regenerative potential. We are particularly interested in age-related macular degeneration (AMD), one of the most common causes of vision loss worldwide. With the help of human retinal organoids and cell systems, we hope to contribute to new therapeutic strategies to prevent vision loss and to restore retinal cell, structure and function.

Our overall goals are to decipher and manipulate mechanisms that control the fate of retinal cells throughout their life. Specifically, we want to find new ways to prevent neuronal cell loss and to restore defects in neural structure and cells. We study the human and mouse retina, an approachable part of the nervous system, to decipher basic mechanisms of neurodegeneration as well as its regenerative potential. We develop human cell and organoid systems and apply them to reproduce pathologic processes – with the ultimate aims to identify new potential therapeutic approaches and targets to prevent neurodegenerative diseases, and to restore them.

Curious? Email me: mike_o.karl(at)tu-dresden.de

Previous and current research

A research highlight that laid the groundwork for our lab was the first evidence for the experimental stimulation of a regenerative response in the mammalian retina: The major type of glia cells in the retina, Müller glia, may produce new neurons (regeneration) in the damaged adult mouse retina in vivo (Karl et al PNAS 2008). However, whether a regenerative response can be elicited in human retina is still unknown.

It is well known that glia at least may gain other functions with beneficial but also detrimental consequences, which either prevent and protect or cause and contribute to retinal diseases, respectively.The regulatory mechanisms that facilitate and limit regeneration, and those controlling other glia functions in pathologies are also still incompletely understood.

Thus, a fundamental question that we are exploring in our research is whether neural scar formation and pathologic function of glia and neurons – highly relevant for AMD and other retinal pathologies in humans, might be part of a misregulated regeneration response or separate entities.

Further, to model neuronal degeneration and regeneration in the human retina, we develop and optimize methods to generate human retinas in the laboratory: Pluripotent stem cells can be differentiated in cell culture to develop 3D organ-like structures – called retinal organoids. We currently apply mouse and human retinal organoids to effectively reproduce retinal pathologic processes, and particularly focus on cone and rod photoreceptor dystrophies and glial pathologies.

Future projects and goals

Our  current overall objectives are to develop human stem cell derived neural organoid and cell systems, specifically for the retina, to apply these to understand mechanisms of neuronal degeneration and regeneration, and thereby to find new therapeutic strategies for a broad patient spectrum, particularly, age-related macular degeneration (AMD).

Interested in detailed aims? Stay tuned!

 

Group leader

© CRTD

Selected publications

Völkner MV, Zschätzsch M, Rostovskaya M, Overall RW, Busskamp V, Anastassiadis K & Karl MO (2016) Retinal organoids from pluripotent stem cells efficiently recapitulate retinogenesis. Stem Cell Reports. 6(4):525-38. Highlighted in: info.cell.com/best-of-stem-cell-reports-2015

Babu S, Münch R, Schäfer P, Oertel P, Sykes A, Zhu Y, Karl MO (2017) Retinal cell death dependent reactive proliferative gliosis in the mouse retina. Scientific Reports 7(1):9517, rdcu.be/vh8P

Löffler K, Schäfer P, Völkner M, Holdt T, Karl MO. Age-dependent Müller glia neurogenic competence in the mouse retina. Glia. 2015;63(10):1809‐1824. doi:10.1002/glia.22846.

Karl MO, Hayes S, Nelson BR, Tan K, Buckingham B, Reh TA. Stimulation of neural regeneration in the mouse retina. Proc Natl Acad Sci U S A. 2008;105(49):19508‐19513. doi:10.1073/pnas.0807453105

Lamba DA, Karl MO, Ware CB, Reh TA. Efficient generation of retinal progenitor cells from human embryonic stem cells. Proc Natl Acad Sci U S A. 2006;103(34):12769‐12774. doi:10.1073/pnas.0601990103

All publications can be found on PubMed and some can be downloaded via ResearchGate.

Lab Activities

www.mokalab.org
www.visionclub.org

FUNDING

DFG SPP1738

DFG SPP2127

BMBF ReSight

BMBF Cleansight

Thanks to our sources of research funding.