How to reprogram human fibroblasts to neurons

Abstract Destruction and death of neurons can lead to neurodegenerative diseases. One possible way to treat neurodegenerative diseases and damage of the nervous system is replacing damaged and dead neurons by cell transplantation. If new neurons can replace the lost neurons, patients may be able to regain the lost functions of memory, motor, and so on. Therefore, acquiring neurons conveniently and efficiently is vital to treat neurological diseases. In recent years, studies on reprogramming human fibroblasts into neurons have emerged one after another, and this paper summarizes all these studies. Scientists find small molecules and transcription factors playing a crucial role in reprogramming and inducing neuron production. At the same time, both the physiological microenvironment in vivo and the physical and chemical factors in vitro play an essential role in the induction of neurons. Therefore, this paper summarized and analyzed these relevant factors. In addition, due to the unique advantages of physical factors in the process of reprogramming human fibroblasts into neurons, such as safe and minimally invasive, it has a more promising application prospect. Therefore, this paper also summarizes some successful physical mechanisms of utilizing fibroblasts to acquire neurons, which will provide new ideas for somatic cell reprogramming.

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Emerging Roles of Sonic Hedgehog in Adult Neurological Diseases: Neurogenesis and Beyond

International Journal of Molecular Sciences ◽

10.3390/ijms19082423 ◽

2018 ◽

Vol 19 (8) ◽

pp. 2423 ◽

Cited By ~ 7

Author(s):

Shang-Der Chen ◽

Jenq-Lin Yang ◽

Wei-Chao Hwang ◽

Ding-I Yang

Keyword(s):

Neurodegenerative Diseases ◽

Sonic Hedgehog ◽

Neural Development ◽

Brain Injuries ◽

Neurological Diseases ◽

Aging Effect ◽

Protective Mechanisms ◽

Age Related

Sonic hedgehog (Shh), a member of the hedgehog (Hh) family, was originally recognized as a morphogen possessing critical characters for neural development during embryogenesis. Recently, however, Shh has emerged as an important modulator in adult neural tissues through different mechanisms such as neurogenesis, anti-oxidation, anti-inflammation, and autophagy. Therefore, Shh may potentially have clinical application in neurodegenerative diseases and brain injuries. In this article, we present some examples, including ours, to show different aspects of Shh signaling and how Shh agonists or mimetics are used to alter the neuronal fates in various disease models, both in vitro and in vivo. Other potential mechanisms that are discussed include alteration of mitochondrial function and anti-aging effect; both are critical for age-related neurodegenerative diseases. A thorough understanding of the protective mechanisms elicited by Shh may provide a rationale to design innovative therapeutic regimens for various neurodegenerative diseases.

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Hybrid graphene–ceramic nanofibre network for spontaneous neural differentiation of stem cells

Interface Focus ◽

10.1098/rsfs.2017.0037 ◽

2018 ◽

Vol 8 (3) ◽

pp. 20170037 ◽

Cited By ~ 6

Author(s):

Jekaterina Kazantseva ◽

Irina Hussainova ◽

Roman Ivanov ◽

Toomas Neuman ◽

Michael Gasik

Keyword(s):

Stem Cells ◽

Culture Media ◽

Neurological Diseases ◽

Human Mesenchymal Stem Cells ◽

Cell Proliferation And Differentiation ◽

Chemical Microenvironment ◽

Specific Culture ◽

Physical And Chemical

A challenge in regenerative medicine is governed by the need to have control over the fate of stem cells that is regulated by the physical and chemical microenvironment in vitro and in vivo . The differentiation of the stem cells into specific lineages is commonly guided by use of specific culture media. For the first time, we demonstrate that human mesenchymal stem cells are capable of turning spontaneously towards neurogenic lineage when seeded on graphene-augmented, highly anisotropic ceramic nanofibres without special differentiation media, contrary to commonly thought requirement of ‘soft’ substrates for the same purpose. Furthermore, pro-inflammatory gene expression is simultaneously suppressed, and expression of factors promoting focal adhesion and monocytes taxis is upregulated. This opens new possibilities of using local topo-mechanical cues of the ‘graphenized’ scaffold surfaces to guide stem cell proliferation and differentiation, which can be used in studies of neurological diseases and cell therapy.

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Probing the 14-3-3 Isoform-Specificity Profile of Interactions Stabilized by Fusicoccin A

10.26434/chemrxiv.12052869.v1 ◽

2020 ◽

Author(s):

James Frederich ◽

Ananya Sengupta ◽

Josue Liriano ◽

Ewa A. Bienkiewicz ◽

Brian G. Miller

Keyword(s):

Protein Interactions ◽

Neurological Diseases ◽

Adapter Proteins ◽

Protein Protein Interactions ◽

Specific Expression ◽

Individual Client ◽

Isoform Specificity ◽

Fusicoccin A

Fusicoccin A (FC) is a fungal phytotoxin that stabilizes protein–protein interactions (PPIs) between 14-3-3 adapter proteins and their phosphoprotein interaction partners. In recent years, FC has emerged as an important chemical probe of human 14-3-3 PPIs implicated in cancer and neurological diseases. These previous studies have established the structural requirements for FC-induced stabilization of 14-3-3·client phosphoprotein complexes; however, the effect of different 14-3-3 isoforms on FC activity has not been systematically explored. This is a relevant question for the continued development of FC variants because there are seven distinct isoforms of 14-3-3 in humans. Despite their remarkable sequence and structural similarities, a growing body of experimental evidence supports both tissue-specific expression of 14-3-3 isoforms and isoform-specific functions <i>in vivo</i>. Herein, we report the isoform-specificity profile of FC <i>in vitro</i>using recombinant human 14-3-3 isoforms and a focused library of fluorescein-labeled hexaphosphopeptides mimicking the C-terminal 14-3-3 recognition domains of client phosphoproteins targeted by FC in cell culture. Our results reveal modest isoform preferences for individual client phospholigands and demonstrate that FC differentially stabilizes PPIs involving 14-3-3s. Together, these data provide strong motivation for the development of non-natural FC variants with enhanced selectivity for individual 14-3-3 isoforms.

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Potential for Treatment of Neurodegenerative Diseases with Natural Products or Synthetic Compounds that Stabilize Microtubules

Current Pharmaceutical Design ◽

10.2174/1381612826666200621171302 ◽

2020 ◽

Vol 26 (35) ◽

pp. 4362-4372

Author(s):

John H. Miller ◽

Viswanath Das

Keyword(s):

Natural Products ◽

Neurodegenerative Diseases ◽

In Vivo Models ◽

Synthetic Compounds ◽

Stabilizing Agents ◽

Animal Models Of Disease ◽

Model Studies ◽

Models Of Disease

No effective therapeutics to treat neurodegenerative diseases exist, despite significant attempts to find drugs that can reduce or rescue the debilitating symptoms of tauopathies such as Alzheimer’s disease, Parkinson’s disease, frontotemporal dementia, amyotrophic lateral sclerosis, or Pick’s disease. A number of in vitro and in vivo models exist for studying neurodegenerative diseases, including cell models employing induced-pluripotent stem cells, cerebral organoids, and animal models of disease. Recent research has focused on microtubulestabilizing agents, either natural products or synthetic compounds that can prevent the axonal destruction caused by tau protein pathologies. Although promising results have come from animal model studies using brainpenetrant natural product microtubule-stabilizing agents, such as paclitaxel analogs that can access the brain, epothilones B and D, and other synthetic compounds such as davunetide or the triazolopyrimidines, early clinical trials in humans have been disappointing. This review aims to summarize the research that has been carried out in this area and discuss the potential for the future development of an effective microtubule stabilizing drug to treat neurodegenerative disease.

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The effect of dipeptidyl peptidase IV on disease-associated microglia phenotypic transformation in epilepsy

Journal of Neuroinflammation ◽

10.1186/s12974-021-02133-y ◽

2021 ◽

Vol 18 (1) ◽

Author(s):

Zhicheng Zheng ◽

Peiyu Liang ◽

Baohua Hou ◽

Xin Lu ◽

Qianwen Ma ◽

...

Keyword(s):

Signaling Pathway ◽

Neurological Diseases ◽

Dipeptidyl Peptidase ◽

Dipeptidyl Peptidase Iv ◽

Sequencing Data ◽

Migration Ability ◽

Dpp4 Inhibitor ◽

Phenotypic Transformation

Abstract Background Accumulating evidence suggests that disease-associated microglia (DAM), a recently discovered subset of microglia, plays a protective role in neurological diseases. Targeting DAM phenotypic transformation may provide new therapeutic options. However, the relationship between DAM and epilepsy remains unknown. Methods Analysis of public RNA-sequencing data revealed predisposing factors (such as dipeptidyl peptidase IV; DPP4) for epilepsy related to DAM conversion. Anti-epileptic effect was assessed by electroencephalogram recordings and immunohistochemistry in a kainic acid (KA)-induced mouse model of epilepsy. The phenotype, morphology and function of microglia were assessed by qPCR, western blotting and microscopic imaging. Results Our results demonstrated that DPP4 participated in DAM conversion and epilepsy. The treatment of sitagliptin (a DPP4 inhibitor) attenuated KA-induced epilepsy and promoted the expression of DAM markers (Itgax and Axl) in both mouse epilepsy model in vivo and microglial inflammatory model in vitro. With sitagliptin treatment, microglial cells did not display an inflammatory activation state (enlarged cell bodies). Furthermore, these microglia exhibited complicated intersections, longer processes and wider coverage of parenchyma. In addition, sitagliptin reduced the activation of NF-κB signaling pathway and inhibited the expression of iNOS, IL-1β, IL-6 and the proinflammatory DAM subset gene CD44. Conclusion The present results highlight that the DPP4 inhibitor sitagliptin can attenuate epilepsy and promote DAM phenotypic transformation. These DAM exhibit unique morphological features, greater migration ability and better surveillance capability. The possible underlying mechanism is that sitagliptin can reduce the activation of NF-κB signaling pathway and suppress the inflammatory response mediated by microglia. Thus, we propose DPP4 may act as an attractive direction for DAM research and a potential therapeutic target for epilepsy.

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Prion Diseases: A Unique Transmissible Agent or a Model for Neurodegenerative Diseases?

Biomolecules ◽

10.3390/biom11020207 ◽

2021 ◽

Vol 11 (2) ◽

pp. 207

Author(s):

Diane L. Ritchie ◽

Marcelo A. Barria

Keyword(s):

Public Health ◽

Neurodegenerative Diseases ◽

Prion Protein ◽

Neurodegenerative Disorders ◽

Prion Diseases ◽

Experimental Models ◽

Misfolded Proteins ◽

Current Evidence

The accumulation and propagation in the brain of misfolded proteins is a pathological hallmark shared by many neurodegenerative diseases such as Alzheimer’s disease (Aβ and tau), Parkinson’s disease (α-synuclein), and prion disease (prion protein). Currently, there is no epidemiological evidence to suggest that neurodegenerative disorders are infectious, apart from prion diseases. However, there is an increasing body of evidence from experimental models to suggest that other pathogenic proteins such as Aβ and tau can propagate in vivo and in vitro in a prion-like mechanism, inducing the formation of misfolded protein aggregates such as amyloid plaques and neurofibrillary tangles. Such similarities have raised concerns that misfolded proteins, other than the prion protein, could potentially transmit from person-to-person as rare events after lengthy incubation periods. Such concerns have been heightened following a number of recent reports of the possible inadvertent transmission of Aβ pathology via medical and surgical procedures. This review will provide a historical perspective on the unique transmissible nature of prion diseases, examining their impact on public health and the ongoing concerns raised by this rare group of disorders. Additionally, this review will provide an insight into current evidence supporting the potential transmissibility of other pathogenic proteins associated with more common neurodegenerative disorders and the potential implications for public health.

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The Potential Neuroprotective Role of Free and Encapsulated Quercetin Mediated by miRNA against Neurological Diseases

Nutrients ◽

10.3390/nu13041318 ◽

2021 ◽

Vol 13 (4) ◽

pp. 1318

Author(s):

Tarek Benameur ◽

Raffaella Soleti ◽

Chiara Porro

Keyword(s):

Inflammatory Responses ◽

Pathological Condition ◽

Neurological Diseases ◽

Neuronal Cell Death ◽

Neuronal Cell ◽

In Vivo Studies ◽

Innovative Drug ◽

Chronic Neuroinflammation

Chronic neuroinflammation is a pathological condition of numerous central nervous system (CNS) diseases such as Parkinson’s disease, Alzheimer’s disease, multiple sclerosis, amyotrophic lateral sclerosis and many others. Neuroinflammation is characterized by the microglia activation and concomitant production of pro-inflammatory cytokines leading to an increasing neuronal cell death. The decreased neuroinflammation could be obtained by using natural compounds, including flavonoids known to modulate the inflammatory responses. Among flavonoids, quercetin possess multiple pharmacological applications including anti-inflammatory, antitumoral, antiapoptotic and anti-thrombotic activities, widely demonstrated in both in vitro and in vivo studies. In this review, we describe the recent findings about the neuroprotective action of quercetin by acting with different mechanisms on the microglial cells of CNS. The ability of quercetin to influence microRNA expression represents an interesting skill in the regulation of inflammation, differentiation, proliferation, apoptosis and immune responses. Moreover, in order to enhance quercetin bioavailability and capacity to target the brain, we discuss an innovative drug delivery system. In summary, this review highlighted an important application of quercetin in the modulation of neuroinflammation and prevention of neurological disorders.

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Further Studies upon Chemical Factors Affecting the Breeding of Anopheles in Trinidad

Bulletin of Entomological Research ◽

10.1017/s0007485300012840 ◽

1934 ◽

Vol 25 (4) ◽

pp. 491-494 ◽

Cited By ~ 3

Author(s):

P. A. Buxton

Keyword(s):

Analytical Study ◽

Chemical Constituents ◽

Physical Factors ◽

Factors Affecting ◽

Early Stages ◽

Freshwater Biology ◽

Chemical Technique ◽

Chemical Factors ◽

Physical And Chemical

During the last decade, entomologists have made progress in understanding the environment in which certain insects live; in particular, we begin to understand the effect of certain physical and chemical factors, which make up a part of the environment. With this gain in knowledge, it is sometimes possible to forecast outbreaks of insects and of diseases conveyed by them, and one can sometimes say that a particular alteration of the environment will result in loss or gain. But so far as mosquitos are concerned, one must admit that though much work has been devoted to the analytical study of the water in which the early stages are passed, the results are disappointing. A consideration of the published work suggests several reasons for this. Investigation into the ecology of the mosquito has had a vogue, and much of it has been done by workers who were isolated and whose knowledge of chemical technique and freshwater biology was limited. Apart from that, the inherent difficulties are great, for the worker must hunt for the limiting chemical and physical factors among a host of others which are doubtless unimportant, and there are few clues to indicate which of the chemical constituents of the water affects the mosquito. The data are therefore voluminous and it is difficult to reduce them to order and present them so that they can be readily understood.

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In Vitro and In Vivo Activities of a Triterpenoid Saponin Extract (PX-6518) from the Plant Maesa balansae against Visceral Leishmania Species

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.48.1.130-136.2004 ◽

2004 ◽

Vol 48 (1) ◽

pp. 130-136 ◽

Cited By ~ 59

Author(s):

Louis Maes ◽

Dirk Vanden Berghe ◽

Nils Germonprez ◽

Ludo Quirijnen ◽

Paul Cos ◽

...

Keyword(s):

Leishmania Donovani ◽

Human Fibroblasts ◽

Subcutaneous Administration ◽

Leishmania Species ◽

Host Cells ◽

Triterpenoid Saponin ◽

Sodium Stibogluconate ◽

Triterpenoid Saponins

ABSTRACT The in vitro and in vivo activities of a mixture of six oleane triterpene saponins, recovered from the methanolic extract of the leaves of the Vietnamese plant Maesa balansae (PX-6518), were evaluated against drug-sensitive visceral Leishmania strains. The in vitro 50% inhibitory concentration (IC50) against intracellular Leishmania infantum amastigotes was 0.04 μg/ml. The cytotoxic concentrations causing 50% cell death (CC50s) were about 1 μg/ml in murine macrophage host cells and >32 μg/ml in human fibroblasts (MRC-5 cell line). Evaluation in the Leishmania donovani BALB/c mouse model indicated that a single subcutaneous administration of 0.4 mg/kg at 1 day after infection reduced liver amastigote burdens by about 95% in all treated animals. If treatment was delayed until 14 days after infection, a dose of 1.6 mg/kg of body weight was required to maintain the same level of activity. Single 250-mg/kg doses of sodium stibogluconate (Pentostam) 1 and 14 days after infection produced comparable efficacies. A single dose of PX-6518 at 2.5 mg/kg administered 5 days before infection was still 100% effective in preventing liver infection, suggesting a particularly long residual action. Spleen and bone marrow could not be cleared by PX-6518 nor sodium stibogluconate. PX-6518 did not show activity after oral dosing at up to 200 mg/kg for 5 days. This study concludes that triterpenoid saponins from M. balansae show promising in vitro and in vivo antileishmanial potential and can be considered as new lead structures in the search for novel antileishmanial drugs.

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DNAJB6b is Downregulated in Synucleinopathies

Journal of Parkinson s Disease ◽

10.3233/jpd-202512 ◽

2021 ◽

pp. 1-13

Author(s):

Jonas Folke ◽

Sertan Arkan ◽

Isak Martinsson ◽

Susana Aznar ◽

Gunnar Gouras ◽

...

Keyword(s):

Neurodegenerative Diseases ◽

Substantia Nigra Pars Compacta ◽

Endogenous Protein ◽

Highly Sensitive ◽

Brain Material ◽

Health And Disease ◽

Isoform B

Background: α-synuclein (α-syn) aggregation contributes to the progression of multiple neurodegenerative diseases. We recently found that the isoform b of the co-chaperone DNAJB6 is a strong suppressor of a-syn aggregation in vivo and in vitro. However, nothing is known about the role of the endogenous isoform b of DNAJB6 (DNAJB6b) in health and disease, due to lack of specific antibodies. Objective: Here we generated a novel anti-DNAJB6b antibody to analyze the localization and expression this isoform in cells, in tissue and in clinical material. Methods: To address this we used immunocytochemistry, immunohistochemistry, as well as a novel quantitative DNAJB6 specific ELISA method. Results: The endogenous protein is mainly expressed in the cytoplasm and in neurites in vitro, where it is found more in dendrites than in axons. We further verified in vivo that DNAJB6b is expressed in the dopaminergic neurons of the substantia nigra pars compacta (SNpc), which is a neuronal subpopulation highly sensitive to α-syn aggregation, that degenerate to a large extend in patients with Parkinson’s disease (PD) and multiple system atrophy (MSA). When we analyzed the expression levels of DNAJB6b in brain material from PD and MSA patients, we found a downregulation of DNAJB6b by use of ELISA based quantification. Interestingly, this was also true when analyzing tissue from patients with progressive supranuclear palsy, a taupathic atypical parkinsonian disorder. However, the total level of DNAJB6 was upregulated in these three diseases, which may indicate an upregulation of the other major isoform of DNAJB6, DNAJB6a. Conclusion: This study shows that DNAJB6b is downregulated in several different neurodegenerative diseases, which makes it an interesting target to further investigate in relation to amyloid protein aggregation and disease progression.

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