Sliding Fibers: Slidable, Injectable, and Gel-like Electrospun Nanofibers as Versatile Cell Carriers

Designing biomaterial systems that can mimic fibrous, natural extracellular matrix is crucial for enhancing the efficacy of various therapeutic tools. Herein, a smart technology of three-dimensional electrospun fibers that can be injected in a minimally invasive manner was developed. Open surgery is currently the only route of administration of conventional electrospun fibers into the body. Coordinating electrospun fibers with a lubricating hydrogel produced fibrous constructs referred to as <i>slid</i>able, <i>in</i>jectable, and <i>g</i>el-like (SLIDING) fibers. These SLIDING fibers could pass smoothly through a catheter and fill any cavity while maintaining their fibrous morphology. Their injectable features were derived from their distinctive rheological characteristics, which were presumably caused by the combinatorial effects of mobile electrospun fibers and lubricating hydrogels. The resulting injectable fibers fostered a highly favorable environment for human neural stem cell (hNSC) proliferation and neurosphere formation within the fibrous structures without compromising hNSC viability. SLIDING fibers demonstrated superior performance as cell carriers in animal stroke models subjected to the middle cerebral artery occlusion (MCAO) stroke model. In this model, SLIDING fiber application extended the survival rate of administered hNSCs by blocking microglial infiltration at the early, acute inflammatory stage. The development of SLIDING fibers will increase the clinical significance of fiber-based scaffolds in many biomedical fields and will broaden their applicability

Sliding Fibers: Slidable, Injectable, and Gel-like Electrospun Nanofibers as Versatile Cell Carriers

Designing biomaterial systems that can mimic fibrous, natural extracellular matrix is crucial for enhancing the efficacy of various therapeutic tools. Herein, a smart technology of three-dimensional electrospun fibers that can be injected in a minimally invasive manner was developed. Open surgery is currently the only route of administration of conventional electrospun fibers into the body. Coordinating electrospun fibers with a lubricating hydrogel produced fibrous constructs referred to as <i>slid</i>able, <i>in</i>jectable, and <i>g</i>el-like (SLIDING) fibers. These SLIDING fibers could pass smoothly through a catheter and fill any cavity while maintaining their fibrous morphology. Their injectable features were derived from their distinctive rheological characteristics, which were presumably caused by the combinatorial effects of mobile electrospun fibers and lubricating hydrogels. The resulting injectable fibers fostered a highly favorable environment for human neural stem cell (hNSC) proliferation and neurosphere formation within the fibrous structures without compromising hNSC viability. SLIDING fibers demonstrated superior performance as cell carriers in animal stroke models subjected to the middle cerebral artery occlusion (MCAO) stroke model. In this model, SLIDING fiber application extended the survival rate of administered hNSCs by blocking microglial infiltration at the early, acute inflammatory stage. The development of SLIDING fibers will increase the clinical significance of fiber-based scaffolds in many biomedical fields and will broaden their applicability

Human Fetal Brain-Derived Neural Stem/Progenitor Cells Grafted into the Adult Epileptic Brain Restrain Seizures in Rat Models of Temporal Lobe Epilepsy

<div><p>Cell transplantation has been suggested as an alternative therapy for temporal lobe epilepsy (TLE) because this can suppress spontaneous recurrent seizures in animal models. To evaluate the therapeutic potential of human neural stem/progenitor cells (huNSPCs) for treating TLE, we transplanted huNSPCs, derived from an aborted fetal telencephalon at 13 weeks of gestation and expanded in culture as neurospheres over a long time period, into the epileptic hippocampus of fully kindled and pilocarpine-treated adult rats exhibiting TLE. <i>In vitro</i>, huNSPCs not only produced all three central nervous system neural cell types, but also differentiated into ganglionic eminences-derived γ-aminobutyric acid (GABA)-ergic interneurons and released GABA in response to the depolarization induced by a high K⁺ medium. NSPC grafting reduced behavioral seizure duration, afterdischarge duration on electroencephalograms, and seizure stage in the kindling model, as well as the frequency and the duration of spontaneous recurrent motor seizures in pilocarpine-induced animals. However, NSPC grafting neither improved spatial learning or memory function in pilocarpine-treated animals. Following transplantation, grafted cells showed extensive migration around the injection site, robust engraftment, and long-term survival, along with differentiation into β-tubulin III⁺ neurons (∼34%), APC-CC1⁺ oligodendrocytes (∼28%), and GFAP⁺ astrocytes (∼8%). Furthermore, among donor-derived cells, ∼24% produced GABA. Additionally, to explain the effect of seizure suppression after NSPC grafting, we examined the anticonvulsant glial cell-derived neurotrophic factor (GDNF) levels in host hippocampal astrocytes and mossy fiber sprouting into the supragranular layer of the dentate gyrus in the epileptic brain. Grafted cells restored the expression of GDNF in host astrocytes but did not reverse the mossy fiber sprouting, eliminating the latter as potential mechanism. These results suggest that human fetal brain-derived NSPCs possess some therapeutic effect for TLE treatments although further studies to both increase the yield of NSPC grafts-derived functionally integrated GABAergic neurons and improve cognitive deficits are still needed.</p></div

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hNSCs express diverse trophic factors. (A) In vitro proliferating and differentiated hNSCs expressed BDNF, NTF3, NTF4, NGF, VEGF, FGF2, and GDNF. (B) Western blotting analysis showed that hNSCs secreted higher levels of BDNF, NTF3, NTF4, NGF, and VEGF into the culture medium than human foreskin fibroblasts secrete. (TIFF 127 kb

Effect of human NSPC grafting on aberrant mossy fiber sprouting in pilocarpine-treated animals.

<p>(A–F) Timm staining exhibits mossy fiber staining from age-matched intact control (A, D), vehicle-injected pilocarpine-treated (B, E) and huNSPCs-transplanted pilocarpine-treated rats (C, F) 3 months following transplantation. D–F are high-magnification views of areas indicated by arrows in A–C, respectively. Arrowheads in D–F indicate the supragranular region of the dentate gyrus. Pilocarpine-treated rats reveal mossy fiber sprouting with an increased density of Timm granules in the supragranular region (B, C, E, F), whereas control rats did not (A, D). Scale bar, 500 µm (C), 100 µm (F). (G) NSPC-transplanted and vehicle injected rats had higher Timm scores than the control group (*<i>P</i><0.05). Error bars, SEM. No significant difference regarding Timm score was found between NSPC- and vehicle-injected groups.</p

Differentiation of human NSPCs following transplantation into the hippocampus of kindled rats.

<p>(A–F) BrdU⁺ grafted cells (green) were co-stained with TUJ1 (red, arrowheads in B, C, E, F) in the CA3 region of the hippocampus (A–C) and fimbria (D–F) in rats. (G–J) hNP⁺ grafted cells (red, arrowheads in G, I, J) were co-localized with TUJ1 (green, arrowheads in H–J) in the hilus of the hippocampus. (J) Orthogonal view from confocal <i>z</i>-series showed that hNP (red) in nuclei and TUJ1 (green) in cytoplasm were expressed in the same cell. (K, M) Under the dual-filter microscope, BrdU⁺ grafted cells co-expressed APC-CC1 in the fimbria (arrows in K), and hNuc⁺ grafted cells co-expressed GFAP in the CA3 region (an arrow in M). Scale bar; 200 µm (A), 20 µm (D), 10 µm (G, J), 20 µm (K).</p

Differentiation of human NSPCs into GABAergic neurons in the hippocampus of kindled rats.

<p>(A–J) BrdU⁺ grafted cells (green, A, C, D, F, G, I, J), were co-labeled with GABA (red, B, C, E, F, H–J), in the molecular and granular layer of the dentate gyrus, hilus of the hippocampus (A–C), and the radiatum layer of the CA3 region (D–J) of rats. (G–I) A large fraction of BrdU⁺ grafted cells co-expressed GABA, as viewed under the dual-filter microscope. (J) Orthogonal view from confocal <i>z</i>-series visualized co-expression of BrdU (green) and GABA (red) in a grafted cell. (K–N) Orthogonal images show that hNP or hNuc⁺ grafted cells (red) co-expressed GABA (green) in different layers of the CA3: the stratum lucidum (K), stratum pyramidale (L and M), and stratum oriens (N). (O–Q) A BrdU⁺ grafted cells (green) were also co-labeled with calbindin2 (CALB2, red) in the stratum oriens around the CA3 area. Scale bar, 200 µm (A), 100 µm (D), 50 µm (G), 10 µm (J), 20 µm (K), 10 µm (O).</p

<i>T</i>₁ and <i>T</i>₂ Dual-Mode MRI Contrast Agent for Enhancing Accuracy by Engineered Nanomaterials

One of the holy grails in biomedical imaging technology is to achieve accurate imaging of biological targets. The development of sophisticated instrumentation and the use of contrast agents have improved the accuracy of biomedical imaging. However, the issue of false imaging remains a problem. Here, we developed a dual-mode artifact filtering nanoparticle imaging agent (AFIA) that comprises a combination of paramagnetic and superparamagnetic nanomaterials. This AFIA has the ability to perform “AND logic gate” algorithm to eliminate false errors (artifacts) from the raw images to enhance accuracy of the MRI. We confirm the artifact filtering capability of AFIA in MRI phantoms and further demonstrate that artifact-free imaging of stem cell migration is possible <i>in vivo</i>

Additional file 8: Table S1. of Human neural stem cells alleviate Alzheimer-like pathology in a mouse model

List of primary antibodies used in immunohistochemistry (IHC) and western blot (WB). (DOCX 28 kb

Additional file 4: Figure S4. of Human neural stem cells alleviate Alzheimer-like pathology in a mouse model

The expression of Aβ-degrading enzymes in both in vivo and in vitro. (A) Transplantation of hNSCs (NSC, n = 7) did not significantly alter the levels of Mme and Ide expression in NSE/APPsw transgenic mice compared with vehicle injection (Veh, n = 6). (B) In vitro expression of Aβ-degrading enzymes in hNSCs. hNSCs under proliferation and differentiation conditions expressed IDE, MME, ECE1 (endothelin converting enzyme 1), ECE2 (endothelin converting enzyme 2), MMP2 (matrix metalloproteinase 2), PLAT (plasminogen activator, tissue), PLAU (plasminogen activator, urokinase), ACE (angiotensin 1 converting enzyme), and CTSB (cathepsin B). On western blot, there were no differences in the levels of Aβ42 in the media containing 1 μM soluble Aβ42 peptides between wells with and without incubation with hNSCs for 2 days. The number of mice (n) in A is indicated. All data represent mean ± SEM. Error bars indicate ± SEM. (TIFF 3170 kb