An increase in reactive oxygen species underlies neonatal cerebellum repair
The neonatal mouse cerebellum shows remarkable regenerative potential upon injury at birth, wherein a subset of Nestin-expressing progenitors (NEPs) undergoes adaptive reprogramming to replenish granule cell progenitors that die. Here, we investigate how the microenvironment of the injured cerebellu...
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2025-08-01
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| Online Access: | https://elifesciences.org/articles/102515 |
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| author | Anna Pakula Salsabiel El Nagar N Sumru Bayin Jens Bager Christensen Daniel Stephen Adam James Reid Richard P Koche Alexandra L Joyner |
| author_facet | Anna Pakula Salsabiel El Nagar N Sumru Bayin Jens Bager Christensen Daniel Stephen Adam James Reid Richard P Koche Alexandra L Joyner |
| author_sort | Anna Pakula |
| collection | DOAJ |
| description | The neonatal mouse cerebellum shows remarkable regenerative potential upon injury at birth, wherein a subset of Nestin-expressing progenitors (NEPs) undergoes adaptive reprogramming to replenish granule cell progenitors that die. Here, we investigate how the microenvironment of the injured cerebellum changes upon injury and contributes to the regenerative potential of normally gliogenic-NEPs and their adaptive reprogramming. Single-cell transcriptomic and bulk chromatin accessibility analyses of the NEPs from injured neonatal cerebella compared to controls show a temporary increase in cellular processes involved in responding to reactive oxygen species (ROS), a known damage-associated molecular pattern. Analysis of ROS levels in cerebellar tissue confirms a transient increase 1 day after injury at postnatal day 1, overlapping with the peak cell death in the cerebellum. In a transgenic mouse line that ubiquitously overexpresses human mitochondrial catalase (mCAT), ROS is reduced 1 day after injury to the granule cell progenitors, and we demonstrate that several steps in the regenerative process of NEPs are curtailed, leading to reduced cerebellar growth. We also provide preliminary evidence that microglia are involved in one step of adaptive reprogramming by regulating NEP replenishment of the granule cell precursors. Collectively, our results highlight that changes in the tissue microenvironment regulate multiple steps in adaptive reprogramming of NEPs upon death of cerebellar granule cell progenitors at birth, highlighting the instructive roles of microenvironmental signals during regeneration of the neonatal brain. |
| format | Article |
| id | doaj-art-56f8744875694934a6cfb79561bf7523 |
| institution | Kabale University |
| issn | 2050-084X |
| language | English |
| publishDate | 2025-08-01 |
| publisher | eLife Sciences Publications Ltd |
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| spelling | doaj-art-56f8744875694934a6cfb79561bf75232025-08-20T03:41:30ZengeLife Sciences Publications LtdeLife2050-084X2025-08-011410.7554/eLife.102515An increase in reactive oxygen species underlies neonatal cerebellum repairAnna Pakula0Salsabiel El Nagar1N Sumru Bayin2https://orcid.org/0000-0003-4371-855XJens Bager Christensen3Daniel Stephen4Adam James Reid5Richard P Koche6https://orcid.org/0000-0002-6820-5083Alexandra L Joyner7https://orcid.org/0000-0001-7090-9605Developmental Biology Program, Sloan Kettering Institute, New York, United StatesDevelopmental Biology Program, Sloan Kettering Institute, New York, United StatesDevelopmental Biology Program, Sloan Kettering Institute, New York, United States; Gurdon Institute, Cambridge University, Cambridge, United Kingdom; Department of Physiology, Development and Neuroscience, Cambridge University, Cambridge, United KingdomGurdon Institute, Cambridge University, Cambridge, United Kingdom; Department of Physiology, Development and Neuroscience, Cambridge University, Cambridge, United KingdomDevelopmental Biology Program, Sloan Kettering Institute, New York, United StatesGurdon Institute, Cambridge University, Cambridge, United KingdomCenter for Epigenetics Research, Memorial Sloan Kettering Cancer Center, New York, United StatesDevelopmental Biology Program, Sloan Kettering Institute, New York, United States; Gurdon Institute, Cambridge University, Cambridge, United Kingdom; Biochemistry, Cell and Molecular Biology Program and Neuroscience Program, Weill Cornell Graduate School of Medical Sciences, New York, United StatesThe neonatal mouse cerebellum shows remarkable regenerative potential upon injury at birth, wherein a subset of Nestin-expressing progenitors (NEPs) undergoes adaptive reprogramming to replenish granule cell progenitors that die. Here, we investigate how the microenvironment of the injured cerebellum changes upon injury and contributes to the regenerative potential of normally gliogenic-NEPs and their adaptive reprogramming. Single-cell transcriptomic and bulk chromatin accessibility analyses of the NEPs from injured neonatal cerebella compared to controls show a temporary increase in cellular processes involved in responding to reactive oxygen species (ROS), a known damage-associated molecular pattern. Analysis of ROS levels in cerebellar tissue confirms a transient increase 1 day after injury at postnatal day 1, overlapping with the peak cell death in the cerebellum. In a transgenic mouse line that ubiquitously overexpresses human mitochondrial catalase (mCAT), ROS is reduced 1 day after injury to the granule cell progenitors, and we demonstrate that several steps in the regenerative process of NEPs are curtailed, leading to reduced cerebellar growth. We also provide preliminary evidence that microglia are involved in one step of adaptive reprogramming by regulating NEP replenishment of the granule cell precursors. Collectively, our results highlight that changes in the tissue microenvironment regulate multiple steps in adaptive reprogramming of NEPs upon death of cerebellar granule cell progenitors at birth, highlighting the instructive roles of microenvironmental signals during regeneration of the neonatal brain.https://elifesciences.org/articles/102515Nestin-expressing progenitorsNEPsgranule cell progenitorsROSregeneration |
| spellingShingle | Anna Pakula Salsabiel El Nagar N Sumru Bayin Jens Bager Christensen Daniel Stephen Adam James Reid Richard P Koche Alexandra L Joyner An increase in reactive oxygen species underlies neonatal cerebellum repair eLife Nestin-expressing progenitors NEPs granule cell progenitors ROS regeneration |
| title | An increase in reactive oxygen species underlies neonatal cerebellum repair |
| title_full | An increase in reactive oxygen species underlies neonatal cerebellum repair |
| title_fullStr | An increase in reactive oxygen species underlies neonatal cerebellum repair |
| title_full_unstemmed | An increase in reactive oxygen species underlies neonatal cerebellum repair |
| title_short | An increase in reactive oxygen species underlies neonatal cerebellum repair |
| title_sort | increase in reactive oxygen species underlies neonatal cerebellum repair |
| topic | Nestin-expressing progenitors NEPs granule cell progenitors ROS regeneration |
| url | https://elifesciences.org/articles/102515 |
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