BDNF Overexpression Enhances Neuronal Activity and Axonal Growth in Human iPSC-Derived Neural Cultures

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Abstract
As the global population continues to age, the incidence of neurodegenerative diseases and neural injuries is increasing, presenting major challenges for healthcare systems. Due to the brain’s limited regenerative capacity, there is an urgent need for strategies that promote neuronal repair and functional integration. Brain-derived neurotrophic factor (BDNF) is a key regulator of synaptic plasticity and neuronal development. In this study, we investigated whether constitutive BDNF expression in human induced pluripotent stem cell (iPSC)-derived neural progenitor cells (NPCs) enhances their neurogenic and integrative potential in vitro. We found that NPCs engineered to overexpress BDNF produced neuronal cultures with increased numbers of mature and spontaneously active neurons, without altering the overall structure or organization of functional networks. Furthermore, BDNF-expressing neurons exhibited significantly greater axonal outgrowth, including directed axon extension in a compartmentalized microfluidic system, suggesting a chemoattractive effect of localized BDNF secretion. These effects were comparable to those observed with the early supplementation of recombinant BDNF. Our results demonstrate that sustained BDNF expression enhances neuronal maturation and axonal projection without disrupting network integrity. These findings support the use of BDNF not only as a therapeutic agent to improve cell therapy outcomes but also as a tool to accelerate the development of functional neural networks in vitro.
Funding Information
  • Ministerio de Ciencia e Innovación (PID2021-126961OB-I00, PID2020-118120RB-I00, PID2023-146800OB-I00, CNS2023-143862, 2021SGR01086, 813851, 964877, CEX2021-001159-M)
  • Generalitat de Catalunya (PID2021-126961OB-I00, PID2020-118120RB-I00, PID2023-146800OB-I00, CNS2023-143862, 2021SGR01086, 813851, 964877, CEX2021-001159-M)
  • European Commission (PID2021-126961OB-I00, PID2020-118120RB-I00, PID2023-146800OB-I00, CNS2023-143862, 2021SGR01086, 813851, 964877, CEX2021-001159-M)
  • European Commission (PID2021-126961OB-I00, PID2020-118120RB-I00, PID2023-146800OB-I00, CNS2023-143862, 2021SGR01086, 813851, 964877, CEX2021-001159-M)
  • Ministerio de Ciencia, Innovación y Universidades (Spain) (PID2021-126961OB-I00, PID2020-118120RB-I00, PID2023-146800OB-I00, CNS2023-143862, 2021SGR01086, 813851, 964877, CEX2021-001159-M)

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