Where Can You Get Stem Cells – The editor and reviewer affiliations are the last to be provided on the Loop research profiles and may not reflect their status at the time of the review.
Brain regenerative strategies through stem cell transplantation hold the potential to promote functional recovery from brain injury caused by trauma or neurodegenerative disease. Most of the positive modulations promoted by stem cells are fueled by bystander effects, namely the increase in neurotrophic factor levels and the reduction of neuroinflammation. But the ultimate goal of cell therapy is to stimulate cell replacement. Therefore, the ability of stem cells to migrate and differentiate into neurons that are later integrated into the host’s neuronal network to replace lost neurons has also been widely investigated. However, as most preclinical studies show, there is little functional integration of graft-derived neurons into host neuronal circuits. Therefore, it is imperative that we better study whole brain cell therapy approaches to better understand what needs to be better understood about the migration and integration of graft-derived neuronal and glial cells before we can expect these therapies to be ready as a viable solution for brain diseases. treatment. Therefore, this review discusses the positive mechanisms induced by cell transplantation in the brain, the limits of adult brain plasticity that may interfere with the neuroregeneration process, as well as some tested strategies to overcome some of these limits. It also considers the efforts made by regulatory authorities to lead to better standardization of preclinical and clinical studies in this field in order to reduce the heterogeneity of the results obtained.
Where Can You Get Stem Cells
In 1868, the German biologist Haeckel coined the term “stem cell” (Haeckel, 1868), suggesting in the History of Natural Creation (Natürliche Schöpfungsgeschichte) that every organism comes from a single cell. Since then, many authors have contributed to the growing body of knowledge in the field of stem cell research. Dunn’s study (1917) was credited as the first clear evidence of successful transplantation of central nervous system (CNS) tissue into the brain of adult mammals, and clear survival of transplanted neonatal cortical tissue (Dunn, 1917). Others followed in his footsteps and provided further evidence of the successful introduction of new brain cells into the adult mammalian brain. But the dogma at the time that the adult brain had no plasticity would prevent a real paradigm shift, and so the field of brain cell transplantation would have to wait until the 1970s and 1980s to really take off (reviewed in Bjorklund). and Stenevi, 1985; Dunnett, 2010).
Allogeneic Stem Cell Transplant: Process, Preparation, Risks
A notable study in the field of neural cell transplantation was the work done by Perlow et al. (1979), who provided the first robust evidence of functional recovery after implantation of fetal rat brain tissue into adult rat brains in which dopaminergic input to the caudate had been destroyed. In addition, Beebe et al. in the same year. (1979) demonstrated for the first time that transplantation of embryonic brain tissue gives rise to extensive axonal networks that form synaptic connections with the host brain. Other landmark studies were the improvements in motor function in patients with Parkinson’s disease (PD) observed by Lindvall et al. (1990), encouraged by the transplantation of grafts of fetal dopaminergic neurons (Lindvall et al., 1992), as well as the more recent observation that a patient with PD, transplanted 24 years later with human cells derived from embryonic ventral mesencephalon, presented. dopaminergic reinnervation derived from putamen transplants (Li et al., 2016).
In addition, important studies in recent decades have encouraged the development of new sources of stem cells that are prone to testing for human transplantation, such as the establishment of lines of human embryonic stem cells (ESC), and cell reprogramming that has led to the development of induced . pluripotent stem cells (iPSC) and their derived cells (Gurdon, 1962; Gurdon et al., 1975; Davis et al., 1987; Thomson et al., 1998; Takahashi and Yamanaka, 2006).
These studies led us to the concept of personalized medicine based on stem cells and the possibility of creating any type of cell from a specialized cell by reprogramming it. So, now we have to ask what the next steps should be to move forward. There is certainly much to know about the potential of stem cells and safety as a regenerative approach, but there is much more to know about the limitations caused by the limited plasticity of the adult brain, which limits the migration and functional integration of sufficient new ends. derived neurons, and glial cells to promote extensive neuroregeneration upon brain injury. In addition, the standardization of preclinical and clinical studies that enables the comparison of results obtained in different studies and causes a faster development of cell-based therapies is also essential.
Cell therapy consists of the use of cells or cell-based products to replace dead or defective cells in order to restore the function of tissues or organs lost in the process of disease or trauma (Lindvall et al., 2004; Kim and de Vellis). , 2009). There are different types of cells that should be considered as a cell source or as precursors of neural progenitors to be used in brain regeneration (Figure 1), namely ESC obtained from the inner cell mass of the embryonic blastocyst, iPSC obtained from reprogrammed cells. , and neural stem cells that can be isolated at different stages of development of the nervous system, such as fetal and adult neural stem cells (Rippon and Bishop, 2004; Takahashi and Yamanaka, 2006; Kim and de Vellis, 2009). All these cell types have strengths and weaknesses (Lo and Parham, 2009; Mendonca et al., 2018) and have been tested in different preclinical studies that have proven to be effective in the treatment of PD (Bjorklund et al., 2002; Wernig et al., 2008; Hargus et al., 2010), Huntington’s disease (HD) (Dunnett et al., 1998; Johann et al., 2007), and Machado-Joseph disease (MJD) (Mendonca et al. , 2015) ). Importantly, some clinical trials have also shown the great potential of these therapies in diseases such as PD (Piccini et al., 1999; Olanow et al., 2003; Li et al., 2016; Bjorklund and Lindvall, 2017) and HD (Freeman. et al., 2000). Despite the large number of preclinical studies and some clinical trials, which describe positive results with cell therapy approaches for brain transplantation, the mechanisms behind these positive modulations and the type of cells that stimulate them are not fully understood.
Stem Cell Transplantation In The Eu
Figure 1. Different sources of stem cells to be used in brain regeneration. Pluripotent stem cells such as ESCs are derived from the inner cell mass of the embryonic blastocyst and iPSCs derived from somatic stem cell reprogramming through various protocols, including the expression of the reprogramming factors Sox-2, Klf4, c-Myc and Oct4. must be modeled and differentiated into different types of neural cells to be transplanted as neural stem cells, which can also be isolated from the nervous system at different stages of development (fetal and adult neural stem cells).
Transplanted cells have been described to improve disease symptoms by integrating new cells derived from the transplant, providing trophic support to endogenous cells, and causing immunomodulation (Figure 2A; Pluchino et al., 2005; Xu et al., 2011; Steinbeck. and Studer, 2015). But the exact contribution of each of these positive mechanisms to the overall improvement observed is unknown.
Figure 2. Therapeutic mechanisms induced by stem cells when transplanted into the diseased brain. Stem cells can act by (A) directly replacing dead and disabled neurons in the neuronal network. (B) Production of neurotrophic factors that support brain cell homeostasis. (C) Cross-talk with brain cells, such as astrocytes and microglia, which play an important role in immune regulation, leading to a reduction in inflammation by reducing pro-inflammatory cytokines such as IL-1β, IL-6, TNF-α and IFN-γ.
Functional integration of graft-derived neurons into host neuronal networks has the potential to fully restore damaged brain areas and rescue behavioral problems. In fact, it has been suggested in various preclinical studies that the observed behavioral recovery is partly the result of the establishment of new synaptic connections between the brain and the transplant (Clarke and Dunnett, 1993; Thompson et al., 2008; Cardoso et al. . . , 2008; al., 2018), and clinical data support this evidence. In a remarkable study, cells derived from the ventral mesencephalon of human embryos were transplanted into a PD patient, and 24 years after the transplant, the authors observed dopaminergic recall of the graft in the putamen (Li et al., 2016). But most studies indicate that only a small number of new neurons derived from transplants functionally integrate into neuronal networks (Cossetti et al., 2012; Forraz et al., 2013; Dunnett and Rosser, 2014). In addition, impaired glia have been described in various conditions such as stroke, multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), PD, and Alzheimer’s disease (AD) (Miller et al., 2004; Lindvall and Kokaia, 2006; Dzamba). et al., 2016; Kokaia et al., 2018), which promotes the replacement of these cells, was tested and led to significant positive results (Windrem et al., 2004; Ericson et al., 2005) (described in more detail in the section “Glial cell transplant” ).
Stem Cells: Cell
Grafted cells can increase the survival and repair of host neurons by secreting neurotrophic factors such as brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), and glial cell-derived neurotrophic factor.
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