Unprecedented Potential for Neural Drug Discovery Based on Self-Organizing hiPSC Platforms.

Human induced pluripotent stem cells (hiPSCs) have transformed conventional drug discovery pathways in recent years. In particular, recent advances in hiPSC biology, including organoid technologies, have highlighted a new potential for neural drug discovery with clear advantages over the use of primary tissues. This is important considering the financial and social burden of neurological health care worldwide, directly impacting the life expectancy of many populations. Patient-derived iPSCs-neurons are invaluable tools for novel drug-screening and precision medicine approaches directly aimed at reducing the burden imposed by the increasing prevalence of neurological disorders in an aging population. 3-Dimensional self-assembled or so-called 'organoid' hiPSCs cultures offer key advantages over traditional 2D ones and may well be gamechangers in the drug-discovery quest for neurological disorders in the coming years.

iPSC for modeling neurodegenerative disorders.

Neurodegenerative disorders such as Parkinson's and Alzheimer's disease, are fundamental health concerns all around the world. The development of novel treatments and new techniques to address these disorders, are being actively studied by researchers and medical personnel. In the present review we will discuss the application of induced Pluripotent Stem Cells (iPSCs) for cell-therapy replacement and disease modelling. The aim of iPSCs is to restore the functionality of the damaged tissue by replacing the impaired cells with competitive ones. To achieve this objective, iPSCs can be properly differentiated into virtually any cell fate and can be strongly translated into human health via in vitro and in vivo disease modeling for the development of new therapies, the discovery of biomarkers for several disorders, the elaboration and testing of new drugs as novel treatments, and as a tool for personalized medicine.

Human Mesenchymal Stem Cells: The Present Alternative for High-Incidence Diseases, Even SARS-Cov-2.

Mesenchymal stem cells (MSCs), defined as plastic adherent cells with multipotent differentiation capacity in vitro, are an emerging and valuable tool to treat a plethora of diseases due to their therapeutic mechanisms such as their paracrine activity, mitochondrial and organelle transfer, and transfer of therapeutic molecules via exosomes. Nowadays, there are more than a thousand registered clinical trials related to MSC application around the world, highlighting MSC role on difficult-to-treat high-incidence diseases such as the current COVID-19, HIV infections, and autoimmune and metabolic diseases. Here, we summarize a general overview of MSCs and their therapeutic mechanisms; also, we discuss some of the novel clinical trial protocols and their results as well as a comparison between the number of registries, countries, and search portals.

Editing the Central Nervous System Through CRISPR/Cas9 Systems.

The translational gap to treatments based on gene therapy has been reduced in recent years because of improvements in gene editing tools, such as the CRISPR/Cas9 system and its variations. This has allowed the development of more precise therapies for neurodegenerative diseases, where access is privileged. As a result, engineering of complexes that can access the central nervous system (CNS) with the least potential inconvenience is fundamental. In this review article, we describe current alternatives to generate systems based on CRISPR/Cas9 that can cross the blood-brain barrier (BBB) and may be used further clinically to improve treatment for neurodegeneration in Parkinson's and Alzheimer's disease (AD).

Implications of human induced pluripotent stem cells in metabolic disorders: from drug discovery toward precision medicine.

Human induced pluripotent stem cells (hiPSCs) enable in vitro high-throughput pharmacological screening assays of diseased tissue. Together with recent genome-wide association studies (GWAS), hiPSCs enable the identification of key mutations for the development of effective treatments based on precise drugs. In concert with CRISPR/Cas9 systems, hiPSC technology can reveal therapeutic targets in metabolic disorders. The ex vivo CRISPR correction of autologous patient-derived hiPSCs has led to the development of replacement cell therapies, providing better patient prognoses.

Recovery from experimental parkinsonism by semaphorin-guided axonal growth of grafted dopamine neurons.

Cell therapy in animal models of Parkinson's disease (PD) is effective after intrastriatal grafting of dopamine (DA) neurons, whereas intranigral transplantation of dopaminergic cells does not cause consistent behavioral recovery. One strategy to promote axonal growth of dopaminergic neurons from the substantia nigra (SN) to the striatum is degradation of inhibitory components such as chondroitin sulphate proteoglycans (CSPG). An alternative is the guidance of DA axons by chemotropic agents. Semaphorins 3A and 3C enhance axonal growth of embryonic stem (ES) cell-derived dopaminergic neurons in vitro, while Semaphorin 3C also attracts them. We asked whether intranigral transplantation of DA neurons, combined with either degradation of CSPG or with grafts of Semaphorin 3-expressing cells, towards the striatum, is effective in establishing a new nigrostriatal dopaminergic pathway in rats with unilateral depletion of DA neurons. We found depolarization-induced DA release in dorsal striatum, DA axonal projections from SN to striatum, and concomitant behavioral improvement in Semaphorin 3-treated animals. These effects were absent in animals that received intranigral transplants combined with Chondroitinase ABC treatment, although partial degradation of CSPG was observed. These results are evidence that Semaphorin 3-directed long-distance axonal growth of dopaminergic neurons, resulting in behavioral improvement, is possible in adult diseased brains.

Axon responses of embryonic stem cell-derived dopaminergic neurons to semaphorins 3A and 3C.

Class 3 Semaphorins are a subfamily of chemotropic molecules implicated in the projection of dopaminergic neurons from the ventral mesencephalon and in the formation of the nigrostriatal pathway (NSP) during embryonic development. In humans, loss of mesencephalic dopaminergic neurons leads to Parkinson's disease (PD). Cell replacement therapy with dopaminergic neurons generated from embryonic stem cells (ES-TH(+)) is being actively explored in models of PD. Among several requisites for this approach to work are adequate reconstruction of the NSP and correct innervation of normal striatal targets by dopaminergic axons. In this work, we characterized the response of ES-TH(+) neurons to semaphorins 3A, 3C, and 3F and compared it with that of tyrosine hidroxylase-positive neurons (TH(+)) obtained from embryonic ventral mesencephalon (VM-TH(+)). We observed that similar proportions of ES-TH(+) and VM-TH(+) neurons express semaphorin receptors neuropilins 1 and 2. Furthermore, the axons of both populations responded very similarly to semaphorin exposure: semaphorin 3A increased axon length, and semaphorin 3C attracted axons and increased their length. These effects were mediated by neuropilins, insofar as addition of blocking antibodies against these proteins reduced the effects on axonal growth and attraction, and only TH(+) axons expressing neuropilins responded to the semaphorins analyzed. The observations reported here show phenotypic similarities between VM-TH(+) and ES-TH(+) neurons and suggest that semaphorins 3A and 3C could be employed to guide axons of grafted ES-TH(+) in therapeutic protocols for PD.