Secretome of Undifferentiated Neural Progenitor Cells Induces Histological and Motor Improvements in a Rat Model of Parkinson's Disease (original) (raw)
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Frontiers in Bioengineering and Biotechnology
Parkinson's disease (PD) is characterized by a selective loss of dopamine (DA) neurons in the human midbrain causing motor dysfunctions. The exact mechanism behind dopaminergic cell death is still not completely understood and, so far, no cure or neuroprotective treatment for PD is available. Recent studies have brought attention to the variety of bioactive molecules produced by mesenchymal stem cells (MSCs), generally referred to as the secretome. Herein, we evaluated whether human MSCs-bone marrow derived (hBMSCs) secretome would be beneficial in a PD pre-clinical model, when compared directly with cell transplantation of hBMSCs alone. We used a 6-hydroxydpomanie (6-OHDA) rat PD model, and motor behavior was evaluated at different time points after treatments (1, 4, and 7 weeks). The impact of the treatments in the recovery of DA neurons was estimated by determining TH-positive neuronal densities in the substantia nigra and fibers in the striatum, respectively, at the end of the behavioral characterization. Furthermore, we determined the effect of the hBMSCs secretome on the neuronal survival of human neural progenitors in vitro, and characterized the secretome through proteomic-based approaches. This work demonstrates that the injection of hBMSCs secretome led to the rescue of DA neurons, when compared to transplantation of hBMSCs themselves, which can explain the recovery of secretome-injected animals' behavioral performance in the staircase test. Moreover, we observed that hBMSCs secretome induces higher levels of in vitro neuronal differentiation. Finally, the proteomic analysis revealed that hBMSCs secrete important exosome-related molecules, such as those related with the ubiquitin-proteasome and histone systems. Overall, this work provided important insights on the potential use of hBMSCs secretome as a therapeutic tool for PD, and further confirms the importance of the secreted molecules rather than the transplantation of hBMSCs for the observed positive effects. These could be likely through normalization of defective processes in PD, namely proteostasis or altered gene transcription, which lately can lead to neuroprotective effects.
Stem cells translational medicine, 2016
Research in the last decade strongly suggests that mesenchymal stem cell (MSC)-mediated therapeutic benefits are mainly due to their secretome, which has been proposed as a possible therapeutic tool for the treatment of Parkinson's disease (PD). Indeed, it has been shown that the MSC secretome increases neurogenesis and cell survival, and has numerous neuroprotective actions under different conditions. Additionally, using dynamic culturing conditions (through computer-controlled bioreactors) can further modulate the MSC secretome, thereby generating a more potent neurotrophic factor cocktail (i.e., conditioned medium). In this study, we have characterized the MSC secretome by proteomic-based analysis, investigating its therapeutic effects on the physiological recovery of a 6hydroxidopamine (6-OHDA) PD rat model. For this purpose, we injected MSC secretome into the substantia nigra (SNc) and striatum (STR), characterizing the behavioral performance and determining histological parameters for injected animals versus untreated groups. We observed that the secretome potentiated the increase of dopaminergic neurons (i.e., tyrosine hydroxylase-positive cells) and neuronal terminals in the SNc and STR, respectively, thereby supporting the recovery observed in the Parkinsonian rats' motor performance outcomes (assessed by rotarod and staircase tests). Finally, proteomic characterization of the MSC secretome (through combined mass spectrometry analysis and Bioplex assays) revealed the presence of important neuroregulatory molecules, namely cystatin C, glia-derived nexin, galectin-1, pigment epithelium-derived factor, vascular endothelial growth factor, brain-derived neurotrophic factor, interleukin-6, and glial cell line-derived neurotrophic factor. Overall, we concluded that the use of human MSC secretome alone was able to partially revert the motor phenotype and the neuronal structure of 6-OHDA PD animals. This indicates that the human MSC secretome could represent a novel therapeutic for the treatment of PD. STEM CELLS TRANSLATIONAL MEDICINE 2016;5:1-13 SIGNIFICANCE It has been suggested that the therapeutic effects of human mesenchymal stem cells (hMSCs) in central nervous system (CNS) regenerative medicine are mediated by the active secretion of bioactive molecules, which is known as the secretome. This study demonstrated that the injection of hMSC secretome in a 6-hydroxidopamine Parkinson's disease (PD) rat model was able to revert the Parkinsonian phenotype, potentiating the recovery of dopaminergic neurons in both the substantia nigra and striatum, thereby supporting the motor recovery observed in the PD rats. This work shows the modulatory role of the hMSC secretome in brain repair, further indicating that such cell-free therapies could represent the basis of future strategies for the treatment of PD.
Cell secretome based approaches in Parkinson’s disease regenerative medicine
Expert Opinion on Biological Therapy, 2018
Introduction: The available therapeutic strategies for Parkinson's disease (PD) rely only on the amelioration of the symptomatology of the disease, lacking neuroprotection or neuroregeneration capacities. Therefore, the development of disease modifying strategies is extremely important for the management of PD in the long term. Areas covered: In this review, the authors provide an overview of the current therapeutic approaches for PD and the emerging use of stem cell transplantation as an alternative. Particularly, the use of the secretome from mesenchymal stem cells (MSCs), as well as some methodologies used for the modulation of their paracrine signaling, will be discussed. Indeed, there is a growing body of literature highlighting the use of paracrine factors and vesicles secreted from different cell populations, for this purpose. Expert opinion: Secretome from MSCs has shown its potential as a therapy for PD. Nevertheless, in the coming years, research should focus in several key aspects to enable the translation of this strategy from the bench to the bedside.
Cells, 2020
Parkinson’s Disease (PD) is characterized by the massive loss of dopaminergic neurons, leading to the appearance of several motor impairments. Current pharmacological treatments, such as the use of levodopa, are yet unable to cure the disease. Therefore, there is a need for novel strategies, particularly those that can combine in an integrated manner neuroprotection and neuroregeneration properties. In vitro and in vivo models have recently revealed that the secretome of mesenchymal stem cells (MSCs) holds a promising potential for treating PD, given its effects on neural survival, proliferation, differentiation. In the present study, we aimed to access the impact of human bone marrow MSCs (hBM-MSCs) secretome in 6-hydroxydopamine (6-OHDA) PD model when compared to levodopa administration, by addressing animals’ motor performance, and substantia nigra (SN), and striatum (STR) histological parameters by tyrosine hydroxylase (TH) expression. Results revealed that hBM-MSCs secretome pe...
Frontiers in Cellular Neuroscience, 2021
Cell therapies represent a promising approach to slow down the progression of currently untreatable neurodegenerative diseases (e.g., Alzheimer's and Parkinson's disease or amyotrophic lateral sclerosis), as well as to support the reconstruction of functional neural circuits after spinal cord injuries. In such therapies, the grafted cells could either functionally integrate into the damaged tissue, partially replacing dead or damaged cells, modulate inflammatory reaction, reduce tissue damage, or support neuronal survival by secretion of cytokines, growth, and trophic factors. Comprehensive characterization of cells and their proliferative potential, differentiation status, and population purity before transplantation is crucial to preventing safety risks, e.g., a tumorous growth due to the proliferation of undifferentiated stem cells. We characterized changes in the proteome and secretome of human neural stem cells (NSCs) during their spontaneous (EGF/FGF2 withdrawal) diffe...
Stem cells may reshape the prospect of Parkinson's disease therapy
Molecular Brain Research, 2005
The concept of cell replacement to compensate for cell loss and restore functionality has entered several disease entities including neurodegenerative disorders. Recent clinical studies have shown that transplantation of fetal dopaminergic (DA) cells into the brain of Parkinson's disease (PD) patients can reduce disease-associated motor deficits. However, the use of fetal tissue is associated with practical and ethical problems including low efficiency, variability in the clinical outcome and controversy regarding the use of fetuses as donor. An alternative cell resource could be embryonic stem (ES) cells, which can be cultivated in unlimited amounts and which have the potential to differentiate into mature DA cells. Several differentiation protocols have been developed, and some progress has been made in understanding the mechanisms underlying DA specification in ES cell development, but the bholy grailQ in this paradigm, which is the production of sufficient amounts of the brightQ therapeutic DA cell, has not yet been accomplished. To achieve this goal, several criteria on the transplanted DA cells need to be fulfilled, mainly addressing cell survival, accurate integration in the brain circuitry, normal function, no tumor formation, and no immunogenicity. Here, we summarize the current state of ES cell-derived DA neurogenesis and discuss the aspects involved in generating an optimal cell source for cell replacement in PD. D
From bench to bed: the potential of stem cells for the treatment of Parkinson’s disease
Cell and Tissue Research, 2008
Parkinson's disease (PD) is the most common movement disorder. The neuropathology is characterized by the loss of dopamine neurons in the substantia nigra pars compacta. Transplants of fetal/embryonic midbrain tissue have exhibited some beneficial clinical effects in open-label trials. Neural grafting has, however, not become a standard treatment for several reasons. First, the supply of donor cells is limited, and therefore, surgery is accompanied by difficult logistics. Second, the extent of beneficial effects has varied in a partly unpredictable manner. Third, some patients have exhibited graft-related side effects in the form of involuntary movements. Fourth, in two major doubleblind placebo-controlled trials, there was no effect of the transplants on the primary endpoints. Nevertheless, neural transplantation continues to receive a great deal of interest, and now, attention is shifting to the idea of using stem cells as starting donor material. In the context of stem cell therapy for PD, stem cells can be divided into three categories: neural stem cells, embryonic stem cells, and other tissue-specific types of stem cells, e.g., bone marrow stem cells. Each type of stem cell is associated with advantages and disadvantages. In this article, we review recent advances of stem cell research of direct relevance to clinical application in PD and highlight the pros and cons of the different sources of cells. We draw special attention to some key problems that face the translation of stem cell technology into the clinical arena.
An Overview of Stem Cell Therapies for Parkinson’s Disease
UTSC's Journal of Natural Sciences, 2021
Parkinson’s disease (PD) is referred to as a neurodegenerative disease which is a disease that targets specific brain regions and is characterized by neuronal death. PD is believed to be caused by the loss of nerve cells in the substantia nigra (SN), a dopamine releasing area (Dickson, 2012). Current treatments are directed at alleviating pain symptoms and slowing down the progression of disease, however, no cure currently exists. Recent advances in stem cell therapies raise new possibilities to treat neurodegenerative diseases. Stem cells have the ability to differentiate into neural cells, and thus, could potentially be used to restore neurogenesis and neuroplasticity (Lunn et al., 2011). There exist several cell types that can be applied in therapy including embryonic stem cells (ESCs), neural stem cells (NSCs), induced pluripotent stem cells (iPSCs), and mesenchymal stem cells (MSCs). PD which has localized neural degeneration to the SN may serve as a better model for stem cell ...
2012
Correspondence: Roger Barker Cambridge Centre for Brain Repair, E.D. Adrian Building, Forvie Site, Robinson Way, Cambridge, CB2 0PY, UK Tel +44 1223 331160 Fax +44 1223 331174 Email rab46@cam.ac.uk Abstract: Currently the mainstay of Parkinson’s disease (PD) therapy is the pharmacological replacement of the loss of the dopaminergic nigrostriatal pathway using drugs such as dopamine agonists and levodopa. Whilst these drugs effectively ameliorate some of the motor features of PD, they do not improve many of the nonmotor features that arise secondary to pathology outside of this system, nor do they slow the progressive neurodegeneration that is a characteristic of the disease. Regenerative therapies for PD seek to fill this therapeutic gap, with cell transplantation being the most explored approach to date. A number of different cell sources have been used in this therapeutic approach, but to date, the most successful has been the use of fetal ventral mesencephalic (VM) tissue that co...
Acta Neuropathologica Communications
It is currently accepted that the human brain has a limited neurogenic capacity and an impaired regenerative potential. We have previously shown the existence of CD271-expressing neural stem cells (NSCs) in the subventricular zone (SVZ) of Parkinson's disease (PD) patients, which proliferate and differentiate towards neurons and glial cells in vitro. To study the molecular profile of these NSCs in detail, we performed RNA sequencing and mass spectrometry on CD271 + NSCs isolated from human post-mortem SVZ and on homogenates of the SVZ. CD271 + cells were isolated through magnetic cell separation (MACS). We first compared the molecular profile of CD271 + NSCs to the SVZ homogenate from control donors and then compared CD271 + cells to CD11b + microglia. These results confirmed their neural stem cell identity. Finally we compared controls and PD patients to establish a specific molecular profile of NSCs and the SVZ in PD. While our transcriptome analysis did not identify any differentially expressed genes in the SVZ between control and PD patients, our proteome analysis revealed several proteins that were differentially expressed in PD. Some of these proteins are involved in cytoskeletal organization and mitochondrial function. Transcriptome and proteome analyses of NSCs from PD revealed changes in the expression of genes and proteins involved in metabolism, transcriptional activity and cytoskeletal organization. Our data suggest that NSCs may transit into a primed-quiescent state, that is in an "alert" non-proliferative phase in PD. Our results not only confirm pathological hallmarks of PD (e.g. impaired mitochondrial function), but also show that the NSCs from SVZ undergo significant changes at both transcriptome and proteome level following PD.