The
formation of a fluid-filled cystic cavity after spinal cord injury
(SCI) is a major obstacle for neural regeneration. In this study,
the post-SCI cavity was bridged by a functional self-assembling peptide
(F-SAP) nanofiber hydrogel coupled with growth factor “cocktail”.
A sustained release of growth factors was achieved by carefully tailoring
the physical hindrances and charge-induced interactions between the
growth factors and the peptide nanofibers. Such an engineering microenvironment
elicited axon regeneration, as determined by tracing of the descending
pathway in the dorsal columns and immunochemical detection of regenerating
axons beyond the lesion. Furthermore, the dynamic spatiotemporal activation
line of endogenous NSCs (eNSCs) after severe SCI was thoroughly investigated.
The results indicated that the growth factor-coupled F-SAP greatly
facilitated eNSC proliferation, neuronal differentiation, maturation,
myelination, and more importantly, the formation of interconnection
with severed descending corticospinal tracts. The robust endogenous
neurogenesis essentially led to the recovery of locomotion and electrophysiological
properties. In conclusion, the growth factor-coupled F-SAP nanofiber
hydrogel elucidated the therapeutic effect of eliciting endogenous
neurogenesis by locally reassembling an extracellular matrix.
Poly(3,4-ethylene
dioxythiophene) (PEDOT) is a promising conductive material widely
used for interfacing with tissues in biomedical fields because of
its unique properties. However, obtaining high charge injection capability
and high stability remains challenging. In this study, pristine carbon
nanotubes (CNTs) modified by dopamine (DA) self-polymerization on
the surface polydopamine (PDA@CNTs) were utilized as dopants of PEDOT
to prepare hybrid films through electrochemical deposition on the
indium tin oxide (ITO) electrode. The PDA@CNTs–PEDOT film of
the nanotube network topography exhibited excellent stability and
strong adhesion to the ITO substrate compared with PEDOT and PEDOT/p-toulene sulfonate. The PDA@CNTs–PEDOT-coated ITO
electrodes demonstrated lower impedance and enhanced charge storage
capacity than the bare ITO. When applying exogenous electrical stimulation
(ES), robust long neurites sprouted from the dorsal root ganglion
(DRG) neurons cultured on the PDA@CNTs–PEDOT film. Moreover,
ES promoted Schwann cell migration out from the DRG spheres and enhanced
myelination. The PDA@CNTs–PEDOT film served as an excellent
electrochemical sensor for the detection of DA in the presence of
biomolecule interferences. Results would shed light into the advancement
of conducting nanohybrids for applications in the multifunctional
bioelectrode in neuroscience.
The fluid‐filled cystic cavity sealed by a dense scar developed following traumatic spinal cord injury (SCI) has been a major obstacle to neural regeneration and functional recovery. Here the transected lesion is bridged using a functional self‐assembling peptide (F‐SAP) hydrogel loaded with membrane‐permeable intracellular sigma peptide (ISP) and intracellular LAR peptide (ILP), targeted at perturbing chondroitin sulfate proteoglycan (CSPG) inhibitory signaling. As compared to F‐SAP hydrogel loaded with chondroitinase ABC, the F‐SAP+ISP/ILP promotes a beneficial anti‐inflammatory response via manipulation of microglia/macrophages infiltration and assembly of extracellular matrix (ECM) molecules into fibrotic matrix rather than scarring tissues. The remodeled ECM creates a permissive environment that supports axon regrowth and the formation of synaptic connections with neurons derived from endogenous neural stem cells. The remodeled networks contribute to functional recovery, as demonstrated by improved hind limb movements and electrophysiological properties. This work proposes a unique mechanism that ECM remodeling induced by CSPG‐manipulation‐based anti‐inflammation can construct a permissive environment for neural regeneration, and shed light on the advancement of manipulation of cascading cellular and molecular events potential for endogenous repair of SCI.
Bone-resorbing activities of osteoclasts (OCs) are highly dependent on actin cytoskeleton remodeling, plasma membrane reorganization, and vesicle trafficking pathways, which are partially regulated by ARF-GTPases. In the present study, the functional roles of Golgi brefeldin A resistance factor 1 (GBF1) are proposed. GBF1 is responsible for the activation of the ARFs family and vesicular transport at the endoplasmic reticulum–Golgi interface in different stages of OCs differentiation. In the early stage, GBF1 deficiency impaired OCs differentiation and was accompanied with OCs swelling and reduced formation of mature OCs, indicating that GBF1 participates in osteoclastogenesis. Using siRNA and the specific inhibitor GCA for GBF1 knockdown upregulated endoplasmic reticulum stress-associated signaling molecules, including BiP, p-PERK, p-EIF2α, and FAM129A, and promoted autophagic Beclin1, Atg7, p62, and LC3 axis, leading to apoptosis of OCs. The present data suggest that, by blocking COPI-mediated vesicular trafficking, GBF1 inhibition caused intense stress to the endoplasmic reticulum and excessive autophagy, eventually resulting in the apoptosis of mature OCs and impaired bone resorption function.
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