Key Takeaways & Executive Findings
- •• LIN28A expression is downregulated in oligodendrocyte precursor cells (OPCs) in a mouse model of preterm white matter injury (PWMI), linking its deficiency to impaired myelinogenesis. • Postnatal knockout of Lin28a in OPCs reduces OPC differentiation and myelin formation, leading to cognitive deficits in mice. • Overexpression of LIN28A in OPCs promotes OPC differentiation and enhances myelinogenesis, rescuing cognitive impairments in PWMI mice. • The study identifies LIN28A as a critical regulator of postnatal myelinogenesis and a potential therapeutic target for treating PWMI.
Abstract
Background: In premature newborn infants, preterm white matter injury (PWMI) causes motor and cognitive disabilities. Accumulating evidence suggests that PWMI may result from defected differentiation of oligodendrocyte precursor cells (OPCs) and impaired maturation of oligodendrocytes. However, the underlying mechanisms remain unclear. Methods: Using RNAscope, we analyzed the expression level of RNA-binding protein LIN28A in individual OPCs. Knockout of one or both alleles of Lin28a in OPCs was achieved by administrating tamoxifen to NG2CreER::Ai14::Lin28aflox/+ or NG2CreER::Ai14::Lin28aflox/flox mice. Lentivirus expressing FLEX-Lin28a was used in NG2CreER mice to overexpress LIN28A in OPCs. A series of behavioral tests were performed to assess the cognitive functions of mice. Two-tailed unpaired t-tests was carried out for statistical analysis between groups. Results: We found that the expression of Lin28a was decreased in OPCs in a PWMI mouse model. Knockout of one or both alleles of Lin28a in OPCs postnatally resulted in reduced OPC differentiation, decreased myelinogenesis and impaired cognitive functions. Supplementing LIN28A in OPCs postnatally was able to promote OPC differentiation and enhance myelinogenesis, thus rescuing the cognitive functions in PWMI mice. Conclusion: Our study reveals that LIN28A is critical in regulating postnatal myelinogenesis. Overexpression of LIN28A in OPCs rescues cognitive deficits in PWMI mice by promoting myelinogenesis, thus providing a potential strategy for the treatment of PWMI.
1. Introduction
Preterm white matter injury (PWMI) is a prevalent form of brain injury in premature newborns, particularly those with low birth weight [1], and has been a leading cause of motor and cognitive impairments in preterm children for decades [2–4]. Although the mechanisms of PWMI remain incompletely understood, a growing body of evidence suggests that PWMI may arise from aberrant differentiation of oligodendrocyte precursor cells (OPCs) and abnormal maturation of oligodendrocytes (OLs) [5]. Thus, transplanting optimized OPCs or optimizing endogenous OPCs to promote myelination in the brain has been considered as potential therapeutic strategies for treating PWMI [6].
LIN28 is an RNA-binding protein that controls self-renewal and differentiation of stem cells, as well as various biological processes [7]. Both LIN28 homologs A and B (LIN28A and LIN28B) block the biogenesis of miRNA let-7 isoforms, and jointly determine cell lineage differentiation by counteracting each other [8]. In the mammalian nervous system, LIN28 plays important roles in regulating neural stem cell proliferation and differentiation during early brain development [9]. Our previous study has demonstrated that increased expression of LIN28A promotes neural stem cell differentiation towards neuronal lineage, but its role in oligodendrocyte development and myelination remains unexplored.
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Xuan Wu, Zhechun Hu, Huimin Yue, Chao Wang, Jie Li, Yinxiang Yang, Zuo Luan, Liang Wang, Ying Shen, Yan Gu (2026). Enhancing myelinogenesis through LIN28A rescues impaired cognition in PWMI mice. Stem Cell Research & Therapy. https://doi.org/10.1186/s13287-025-04267-9
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Frequently Asked Questions
What is preterm white matter injury (PWMI)?
PWMI is a common brain injury in premature infants, particularly those with low birth weight, leading to motor and cognitive disabilities. It is associated with impaired differentiation of oligodendrocyte precursor cells and abnormal maturation of oligodendrocytes.
How does LIN28A affect myelinogenesis?
LIN28A is an RNA-binding protein that promotes oligodendrocyte precursor cell differentiation and enhances myelin formation. Its expression is decreased in PWMI, and restoring LIN28A in OPCs rescues cognitive deficits by promoting myelinogenesis.
What was the experimental approach in this study?
The study used RNAscope to analyze LIN28A expression in OPCs, conditional knockout mice to delete Lin28a in OPCs, and lentivirus-mediated overexpression to restore LIN28A. Behavioral tests assessed cognitive functions.
What are the key findings of the study?
The study found that LIN28A is critical for postnatal myelinogenesis. Knockout of Lin28a in OPCs impaired differentiation and cognition, while overexpression rescued these deficits in a PWMI mouse model.
What is the clinical significance of this research?
The findings suggest that targeting LIN28A in OPCs could be a potential therapeutic strategy for treating PWMI and improving cognitive outcomes in preterm infants.
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