The postischemic environment differentially impacts teratoma or tumor formation after transplantation of human embryonic stem cell-derived neural progenitors

Risk of tumorigenesis is a major obstacle to human embryonic and induced pluripotent stem cell therapy. Likely linked to the stage of differentiation of the cells at the time of implantation, formation of teratoma/tumors can also be influenced by factors released by the host tissue. We have analyzed the relative effects of the stage of differentiation and the postischemic environment on the formation of adverse structures by transplanted human embryonic stem cell-derived neural progenitors

Human Galectins Induce Conversion of Dermal Fibroblasts into Myofibroblasts and Production of Extracellular Matrix: Potential Application in Tissue Engineering and Wound Repair

Members of the galectin family of endogenous lectins are potent adhesion/growth-regulatory effectors. Their multi-functionality opens possibilities for their use in bioapplications. We studied whether human galectins induce the conversion of human dermal fibroblasts into myofibroblasts (MFBs) and the production of a bioactive extracellular matrix scaffold is suitable for cell culture. Testing a panel of galectins of all three subgroups, including natural and engineered variants, we detected activity for the proto-type galectin-1 and galectin-7, the chimera-type galectin-3 and the tandem-repeat-type galectin-4. The activity of galectin-1 required the integrity of the carbohydrate recognition domain. It was independent of the presence of TGF-beta 1, but it yielded an additive effect. The resulting MFBs, relevant, for example, for tumor progression, generated a matrix scaffold rich in fibronectin and galectin-1 that supported keratinocyte culture without feeder cells. Of note, keratinocytes cultured on this substratum presented a stem-like cell phenotype with small size and keratin-19 expression. In vivo in rats, galectin-1 had a positive effect on skin wound closure 21 days after surgery. In conclusion, we describe the differential potential of certain human galectins to induce the conversion of dermal fibroblasts into MFBs and the generation of a bioactive cell culture substratum. Copyright (C) 2011 S. Karger AG, Base

The use of dopamine-hyaluronate associate-coated maghemite nanoparticles to label cells

Sodium hyaluronate (HA) was associated with dopamine (DPA) and introduced as a coating for maghemite (γ-Fe2O3) nanoparticles obtained by the coprecipitation of iron(II) and iron(III) chlorides and oxidation with sodium hypochlorite. The effects of the DPA anchorage of HA on the γ-Fe2O3 surface on the physicochemical properties of the resulting colloids were investigated. Nanoparticles coated at three different DPA-HA/γ-Fe2O3 and DPA/HA ratios were chosen for experiments with rat bone marrow mesenchymal stem cells and human chondrocytes. The nanoparticles were internalized into rat bone marrow mesenchymal stem cells via endocytosis as confirmed by Prussian Blue staining. The efficiency of mesenchymal stem cell labeling was analyzed. From among the investigated samples, efficient cell labeling was achieved by using DPA-HA-γ-Fe2O3 nanoparticles with DPA-HA/γ-Fe2O3 = 0.45 (weight/ weight) and DPA/HA = 0.038 (weight/weight) ratios. The particles were used as a contrast agent in magnetic resonance imaging for the labeling and visualization of cells

Human conditionally immortalized neural stem cells improve locomotor function after spinal cord injury in the rat

INTRODUCTION: A growing number of studies have highlighted the potential of stem cell and more-differentiated neural cell transplantation as intriguing therapeutic approaches for neural repair after spinal cord injury (SCI). METHODS: A conditionally immortalized neural stem cell line derived from human fetal spinal cord tissue (SPC-01) was used to treat a balloon-induced SCI. SPC-01 cells were implanted into the lesion 1 week after SCI. To determine the feasibility of tracking transplanted stem cells, a portion of the SPC-01 cells was labeled with poly-L-lysine-coated superparamagnetic iron-oxide nanoparticles, and the animals grafted with labeled cells underwent magnetic resonance imaging. Functional recovery was evaluated by using the BBB and plantar tests, and lesion morphology, endogenous axonal sprouting and graft survival, and differentiation were analyzed. Quantitative polymerase chain reaction (qPCR) was used to evaluate the effect of transplanted SPC-01 cells on endogenous regenerative processes. RESULTS: Transplanted animals displayed significant motor and sensory improvement 2 months after SCI, when the cells robustly survived in the lesion and partially filled the lesion cavity. qPCR revealed the increased expression of rat and human neurotrophin and motor neuron genes. The grafted cells were immunohistologically positive for glial fibrillary acidic protein (GFAP); however, we found 25% of the cells to be positive for Nkx6.1, an early motor neuron marker. Spared white matter and the robust sprouting of growth-associated protein 43 (GAP43)(+) axons were found in the host tissue. Four months after SCI, the grafted cells matured into Islet2(+) and choline acetyltransferase (ChAT)(+) neurons, and the graft was grown through with endogenous neurons. Grafted cells labeled with poly-L-lysine-coated superparamagnetic nanoparticles before transplantation were detected in the lesion on T(2)-weighted images as hypointense spots that correlated with histologic staining for iron and the human mitochondrial marker MTCO2. CONCLUSIONS: The transplantation of SPC-01 cells produced significant early functional improvement after SCI, suggesting an early neurotrophic action associated with long-term restoration of the host tissue, making the cells a promising candidate for future cell therapy in patients with SCI

Transplantation of Neural Precursors Derived from Induced Pluripotent Cells Preserve Perineuronal Nets and Stimulate Neural Plasticity in ALS Rats.

A promising therapeutic strategy for amyotrophic lateral sclerosis (ALS) treatment is stem cell therapy. Neural progenitors derived from induced pluripotent cells (NP-iPS) might rescue or replace dying motoneurons (MNs). However, the mechanisms responsible for the beneficial effect are not fully understood. The aim here was to investigate the mechanism by studying the effect of intraspinally injected NP-iPS into asymptomatic and early symptomatic superoxide dismutase (SOD)1G93A transgenic rats. Prior to transplantation, NP-iPS were characterized in vitro for their ability to differentiate into a neuronal phenotype. Motor functions were tested in all animals, and the tissue was analyzed by immunohistochemistry, qPCR, and Western blot. NP-iPS transplantation significantly preserved MNs, slowed disease progression, and extended the survival of all treated animals. The dysregulation of spinal chondroitin sulfate proteoglycans was observed in SOD1G93A rats at the terminal stage. NP-iPS application led to normalized host genes expression (versican, has-1, tenascin-R, ngf, igf-1, bdnf, bax, bcl-2, and casp-3) and the protection of perineuronal nets around the preserved MNs. In the host spinal cord, transplanted cells remained as progenitors, many in contact with MNs, but they did not differentiate. The findings suggest that NP-iPS demonstrate neuroprotective properties by regulating local gene expression and regulate plasticity by modulating the central nervous system (CNS) extracellular matrix such as perineuronal nets (PNNs)

Chronic alcohol consumption alters extracellular space geometry and transmitter diffusion in the brain

[EN] Already moderate alcohol consumption has detrimental long-term effects on brain function. However, how alcohol produces its potent addictive effects despite being a weak reinforcer is a poorly understood conundrum that likely hampers the development of successful interventions to limit heavy drinking. In this translational study, we demonstrate widespread increased mean diffusivity in the brain gray matter of chronically drinking humans and rats. These alterations appear soon after drinking initiation in rats, persist into early abstinence in both species, and are associated with a robust decrease in extracellular space tortuosity explained by a microglial reaction. Mathematical modeling of the diffusivity changes unveils an increased spatial reach of extrasynaptically released transmitters like dopamine that may contribute to alcohol's progressively enhanced addictive potencyThis work was supported by the European Union's Horizon 2020 research and innovation program (668863-SyBil-AA) and the ERA-NET NEURON program (FKZ 01EW1112-TRANSALC and PIM2010ERN-00679), as well as the Spanish State Research Agency through the Severo Ochoa Program for Centres of Excellence in R&D (SEV-2017-0723), the Deutsche Forschungsgemeinschaft (center grant TRR265-B08), and the Czech Science Foundation (GACR; grant no. 16-10214S to L.V.). S.C. and D.M. further acknowledge financial support from the Ministerio de Economia y Competitividad (MINECO) and FEDER funds under grant nos. BFU2015-64380-C2-1-R, BFU2015-64380-C2-2-R, and PGC2018-101055-B-I00 and the Generalitat Valenciana through the Prometeo Program (PROMETEO/2019/015). S.C. also acknowledges support of the Ministerio de Sanidad, Servicios Sociales e Igualdad (#2017I065). E.S. acknowledges financial support from the Slovak Research and Development Agency (APVV-17-0642). S.D.S. is supported by a NARSAD Young Investigator Grant (grant no. 25104), by the European Research Council through a Marie Sklodowska-Curie Individual Fellowship (grant no. 749506), and by the Generalitat Valenciana grant SEJI/2019/038. R.C. is supported by the NIAAA grant AA017447. W.H.S acknowledges support from the Bundesministerium fur Bildung und Forschung (BMBF; FKZ: 031L0190A, 01ZX1909CA).De Santis, S.; Cosa-Liñán, A.; Garcia-Hernandez, R.; Dmytrenko, L.; Vargova, L.; Vorisek, I.; Stopponi, S.... (2020). Chronic alcohol consumption alters extracellular space geometry and transmitter diffusion in the brain. Science Advances. 6(26):1-12. https://doi.org/10.1126/sciadv.aba0154S11262

Neuroprotective Potential of Cell-Based Therapies in ALS: From Bench to Bedside

Motor neurons (MN) degeneration is a main feature of amyotrophic lateral sclerosis (ALS), a neurological disorder with a progressive course. The diagnosis of ALS is essentially a clinical one. Most common symptoms include a gradual neurological deterioration that reflect the impairment and subsequent loss of muscle functions. Up-to-date ALS has no therapy that would prevent or cure a disease. Modern therapeutic strategies comprise of neuroprotective treatment focused on antiglutamatergic, antioxidant, antiapoptotic, and anti-inflammatory molecules. Stem cells application and gene therapy has provided researchers with a powerful tool for discovery of new mechanisms and therapeutic agents, as well as opened new perspectives for patients and family members. Here, we review latest progress made in basic, translational and clinical stem cell research related to the ALS. We overviewed results of preclinical and clinical studies employing cell-based therapy to treat neurodegenerative disorders. A special focus has been made on the neuroprotective properties of adult mesenchymal stromal cells (MSC) application into ALS patients. Finally, we overviewed latest progress in the field of embryonic and induced pluripotent stem cells used for the modeling and application during neurodegeneration in general and in ALS in particular