TY - JOUR
T1 - Neuronal Replenishment via Hydrogel-Rationed Delivery of Reprogramming Factors
AU - Mahmoudi, Negar
AU - Wang, Yi
AU - Moriarty, Niamh
AU - Ahmed, Noorya Y.
AU - Dehorter, Nathalie
AU - Lisowski, Leszek
AU - Harvey, Alan R.
AU - Parish, Clare L.
AU - Williams, Richard J.
AU - Nisbet, David R.
PY - 2024/1/30
Y1 - 2024/1/30
N2 - The central nervous system’s limited capacity for regeneration often leads to permanent neuronal loss following injury. Reprogramming resident reactive astrocytes into induced neurons at the site of injury is a promising strategy for neural repair, but challenges persist in stabilizing and accurately targeting viral vectors for transgene expression. In this study, we employed a bioinspired self-assembling peptide (SAP) hydrogel for the precise and controlled release of a hybrid adeno-associated virus (AAV) vector, AAVDJ, carrying the NeuroD1 neural reprogramming transgene. This method effectively mitigates the issues of high viral dosage at the target site, off-target delivery, and immunogenic reactions, enhancing the vector’s targeting and reprogramming efficiency. In vitro, this vector successfully induced neuron formation, as confirmed by morphological, histochemical, and electrophysiological analyses. In vivo, SAP-mediated delivery of AAVDJ-NeuroD1 facilitated the trans-differentiation of reactive host astrocytes into induced neurons, concurrently reducing glial scarring. Our findings introduce a safe and effective method for treating central nervous system injuries, marking a significant advancement in regenerative neuroscience.
AB - The central nervous system’s limited capacity for regeneration often leads to permanent neuronal loss following injury. Reprogramming resident reactive astrocytes into induced neurons at the site of injury is a promising strategy for neural repair, but challenges persist in stabilizing and accurately targeting viral vectors for transgene expression. In this study, we employed a bioinspired self-assembling peptide (SAP) hydrogel for the precise and controlled release of a hybrid adeno-associated virus (AAV) vector, AAVDJ, carrying the NeuroD1 neural reprogramming transgene. This method effectively mitigates the issues of high viral dosage at the target site, off-target delivery, and immunogenic reactions, enhancing the vector’s targeting and reprogramming efficiency. In vitro, this vector successfully induced neuron formation, as confirmed by morphological, histochemical, and electrophysiological analyses. In vivo, SAP-mediated delivery of AAVDJ-NeuroD1 facilitated the trans-differentiation of reactive host astrocytes into induced neurons, concurrently reducing glial scarring. Our findings introduce a safe and effective method for treating central nervous system injuries, marking a significant advancement in regenerative neuroscience.
KW - direct reprogramming
KW - glial scar
KW - neural regeneration
KW - neurogenesis
KW - self-assembling peptide-based hydrogels
KW - trans-differentiation
UR - http://www.scopus.com/inward/record.url?scp=85183479925&partnerID=8YFLogxK
U2 - 10.1021/acsnano.3c11337
DO - 10.1021/acsnano.3c11337
M3 - Article
C2 - 38221746
AN - SCOPUS:85183479925
SN - 1936-0851
VL - 18
SP - 3597
EP - 3613
JO - ACS Nano
JF - ACS Nano
IS - 4
ER -