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Mismatch Repair01:36

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Organisms are capable of detecting and fixing nucleotide mismatches that occur during DNA replication. This sophisticated process requires identifying the new strand and replacing the erroneous bases with correct nucleotides. Mismatch repair is coordinated by many proteins in both prokaryotes and eukaryotes.
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In order to be passed through generations, genomic DNA must be undamaged and error-free. However, every day, DNA in a cell undergoes several thousand to a million damaging events by natural causes and external factors. Ionizing radiation such as UV rays, free radicals produced during cellular respiration, and hydrolytic damage from metabolic reactions can alter the structure of DNA. Damages caused include single-base alteration, base dimerization, chain breaks, and cross-linkage.
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One of the common DNA damages is the chemical alteration of single bases by alkylation, oxidation, or deamination. The altered bases cause mispairing and strand breakage during replication. This type of damage causes minimal change to the DNA double helix structure and can be repaired by the base excision repair (BER) pathways. BER corrects damaged DNA sequences by removing the damaged base and restoring the original base sequence using the complementary strand as a template.
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Since the discovery of the two BER pathways, there has been a debate about how a cell chooses one pathway over the other and the factors determining this selection. Numerous in vitro experiments have pointed out multiple determinants for the sub-pathway selection. These are:
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Related Experiment Video

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Author Spotlight: Analyzing the Synaptic Ultrastructure in Mature Retinal Organoids Using TEM
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Organoid technology for retinal repair.

Sílvia Llonch1, Madalena Carido2, Marius Ader1

  • 1CRTD/Center for Regenerative Therapies Dresden, Center for Molecular and Cellular Bioengineering (CMCB), Technische Universität Dresden, Fetscherstraße 105, 01307 Dresden, Germany.

Developmental Biology
|January 3, 2018
PubMed
Summary

Vision loss from retinal degeneration is irreversible. This review explores using stem cell-derived retinal organoids for photoreceptor transplantation to restore vision, discussing progress and challenges for clinical application.

Keywords:
PhotoreceptorPluripotent stem cellsRetinal degenerationRetinal organoidTransplantation

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Area of Science:

  • Ophthalmology
  • Regenerative Medicine
  • Stem Cell Biology

Background:

  • Photoreceptor damage causes vision impairment and blindness in diseases like Retinitis Pigmentosa and age-related macular degeneration.
  • Current treatments cannot halt photoreceptor loss or regenerate damaged retinal tissue in humans.
  • Cell replacement via photoreceptor transplantation offers a potential therapeutic strategy for retinal degeneration.

Purpose of the Study:

  • To review milestones in generating transplantable photoreceptor precursors from pluripotent stem cell (PSC)-derived retinal organoids.
  • To discuss recent pre-clinical transplantation studies using organoid-derived photoreceptors.
  • To summarize challenges for clinical application of photoreceptor transplantation.

Main Methods:

  • Utilizing 3D culture systems to generate human retinal organoids from PSCs.
  • Analyzing pre-clinical transplantation studies involving organoid-derived photoreceptors.
  • Comparing organoid-derived photoreceptor data with in vivo studies using primary photoreceptors.

Main Results:

  • Significant progress has been made in generating transplantable photoreceptor precursors from PSC-derived retinal organoids.
  • Pre-clinical studies demonstrate the potential of organoid-derived photoreceptors in transplantation models.
  • Advancements in PSC technology have increased access to human retinal material for research.

Conclusions:

  • Photoreceptor transplantation using PSC-derived retinal organoids is a promising approach for treating retinal degeneration.
  • Further research is needed to overcome remaining challenges for successful clinical translation.
  • This strategy holds potential for restoring vision in patients with irreversible blindness.