Adult Stem Cells and Induced Pluripotent Stem Cells for Stroke Treatment

This moon shot is the best use of following the stroke strategy to get everyone 100% recovered? I don't think so.

But I'd rather they tackle known problems first. Like research that stops the 5 causes of the neuronal cascade of death in the first week. Much more likely to succeed.

Adult Stem Cells and Induced Pluripotent Stem Cells for Stroke Treatment

Héctor Fernández-Susavila, Ana Bugallo-Casal, José Castillo and Francisco Campos^*

• Clinical Neuroscience Research Laboratory, Health Research Institute of Santiago de Compostela (IDIS), Santiago de Compostela, Spain

Stroke is the main cause of disability and death in the world within neurological diseases. Despite such a huge impact, enzymatic, and mechanical recanalization are the only treatments available so far for ischemic stroke, but only <20% of patients can benefit from them. The use of stem cells as a possible cell therapy in stroke has been tested for years. The results obtained from these studies, although conflicting or controversial in some aspects, are promising. In the last few years, the recent development of the induced pluripotent stem cells has opened new possibilities to find new cell therapies against stroke. In this review, we will provide an overview of the state of the art of cell therapy in stroke. We will describe the current situation of the most employed stem cells and the use of induced pluripotent stem cells in stroke pathology. We will also present a summary of the different clinical trials that are being carried out or that already have results on the use of stem cells as a potential therapeutic intervention for stroke.

Introduction

From the moment that the capacity of differentiation and self-renewal of stem cells became known, their use as cell therapy for a wide range of diseases has been considered. The international community has focused on this idea, starting a revolution in the study of stem cells (1). This revolution led to several important discoveries that, step by step, paved the way to convert cell therapy into reality. But the greatest discovery was made in 2006 when Yamanaka and Takahashi were able, for the first time, to generate induced pluripotent stem cells (iPSCs) from adult somatic cells by inducing the artificial expression of four transcriptional factors: OCT4, SOX2, c-MYC, and KLF4 (2). This new approach provided a considerable resource of human pluripotent stem cells that could be propagated during long-term culture and yet be differentiated to a variety of lineages representatives of the three embryonic germ layers, solving the ethical limitations caused by the use of human embryonic stem cells.

In addition, the generation of human iPSCs from different somatic cells of patients and the subsequent differentiation to the affected cell lineage has allowed the recapitulation of features of genetic pathologies through in vitro disease modeling and the discovery of new treatments directly tested on these human cells. Recently, the combination of iPSCs with the advances in genome editing techniques, such as the clustered regularly interspaced short palindromic repeat (CRISPR) system, has also provided a promising way to repair putative causative alleles in patient lines into a healthy cell line for future autologous cell therapy (3, 4) (Figure 1).

FIGURE 1

Figure 1. iPSCs modeling scheme. Adult somatic cells (e.g., blood cells) are collected from the patient, reprogrammed and derived to the affected cell types (e.g., endothelial cells, muscle cells, neurons, or astrocytes), which are co-cultured in vitro, opening the possibility to perform several studies directly on the patient's own cells. Adapted from Servier Medical Art by Servier is licensed under a Creative Commons Attribution 3.0 Unported License (https://smart.servier.com/).

The development of human iPSCs has also opened a new opportunity for those neurological diseases where the affected neuronal type is well-known or the genetic cause of the pathology is well-described such as (i) Alzheimer's (5, 6), (ii) Parkinson's (7, 8), (iii) amyotrophic lateral sclerosis (9), or (iv) Huntington disease (10). In these pathologies, iPSCs have been used to generate neuronal cell lines to recapitulate and study the mechanics of the pathology in in vitro models or to evaluate their neurorecovery capability.

In the field of stroke, like other stem cells, iPSCs have been used as a neuroprotective cell therapy (mainly based on their immunomodulatory capacity) or as a neuroreparative therapy (by inducing neurogenesis, angiogenesis, synaptogenesis, modulation of the immune response, or transdifferentiation) (Figure 2). Besides its neuroprotective or neuroreparative application, the use of iPSCs for stroke modeling has been poorly exploited mainly because this is a neurological pathology with multiple affected cells types and reduced genetic component, compared to other neurological diseases such as Alzheimer's or Parkinson's. However, the use of iPSCs has been recently explored to model neurovascular pathologies associated with risk of stroke (11, 12), opening a promising approach in the study of these neurovascular diseases.

FIGURE 2

Figure 2. Scheme of all the main effects promoted by stem cells in stroke. By intraparenchymal injection or i.v./i.a. routes, stem cells induce neurogenesis, transdifferentiation, angiogenesis, synaptogenesis, and immune modulation by attracting or releasing trophic substances to the infarcted area. Adapted from Servier Medical Art by Servier is licensed under a Creative Commons Attribution 3.0 Unported License (https://smart.servier.com/).

In this review, we offer a general overview of the use of adult stem cells and iPSCs in stroke, addressing the main problems and the main clinical trials that already present results.

Adult Stem Cell Therapy in Stroke

Stroke, resulting from the interruption of blood supply to the brain, is the leading cause of disability and death in the world within neurological diseases despite a decrease in its mortality rate (13). Pharmacological or mechanical reperfusion therapies are the most effective treatments during the acute phase of ischemic stroke and it is associated with good outcome in 50–70% of cases. However, these treatments are only applicable to <20% of patients because of the short therapeutic window and side effects (14).

Stem-cell-based therapies have emerged as a promising tool for the treatment of both acute and delayed phases of stroke owing to their multipotentiality, ability to release growth factors, and immunomodulatory capacities. Thus, this transdifferentiation is able to produce cells with a neural lineage; induce neurogenesis, angiogenesis, and synaptogenesis; and activate endogenous restorative processes through the production of cytokines and trophic factors. Moreover, the regulation of cerebral blood flow (CBF), the blood–brain barrier (BBB), and other neuroprotective mechanisms, such as the reduction of apoptosis, inflammation, and demyelination or the increase of astrocyte survival, have also been described as beneficial after stroke (15).

While the technology of the iPSCs is quite new and deeper studies are being carried out to know its real translationality, studies with adult stem cells have been performed for much longer, and there is more information about their use in cell therapy for stroke. Furthermore, there are already clinical trials going on and even closed with adult stem cells. Focusing on stroke, the most frequently used stem cells are the mesenchymal stem cells (MSCs), due to their great trophic capabilities, and the neural stem cells (NSCs), because of their neurorecovery activity (15).

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