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. 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). 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. 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). 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). 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. 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. 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 revolution led to several important discoveries that, step by step, paved the way to convert cell therapy into reality. The international community has focused on this idea, starting a revolution in the study of stem cells ( 1). 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.įrom 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. We will describe the current situation of the most employed stem cells and the use of induced pluripotent stem cells in stroke pathology. In this review, we will provide an overview of the state of the art of cell therapy in stroke. 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. The results obtained from these studies, although conflicting or controversial in some aspects, are promising. The use of stem cells as a possible cell therapy in stroke has been tested for years. 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. Stroke is the main cause of disability and death in the world within neurological diseases. Clinical Neuroscience Research Laboratory, Health Research Institute of Santiago de Compostela (IDIS), Santiago de Compostela, Spain.Héctor Fernández-Susavila Ana Bugallo-Casal José Castillo Francisco Campos *
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