Co-Transplantation of Adipose Tissue-Derived Stromal Cells and Olfactory Ensheathing Cells for Spinal Cord Injury Repair.

Patients suffering from spinal cord injury (SCI) still have a dismal prognosis. Despite all the efforts developed in this area, currently there are no effective treatments. Therefore, cell therapies have been proposed as a viable alternative to the current treatments used. Adipose tissue-derived stromal cells (ASCs) and olfactory ensheathing cells (OECs) have been used with promising results in different models of SCI, namely due to the regenerative properties of the secretome of the first, and the guidance capability of the second. Using an in vitro model of axonal growth, the dorsal root ganglia explants, we demonstrated that OECs induce neurite outgrowth mainly through cell-cell interactions, while ASCs' effects are strongly mediated by the release of paracrine factors. A proteomic analysis of ASCs' secretome revealed the presence of proteins involved in VEGF, PI3K, and Cadherin signaling pathways, which may be responsible for the effects observed. Then, the cotransplantation of ASCs and OECs showed to improve motor deficits of SCI-rats. Particular parameters of movement such as stepping, coordination, and toe clearance were improved in rats that received the transplant of cells, in comparison to nontreated rats. A histological analysis of the spinal cord tissues revealed that transplantation of ASCs and OECs had a major effect on the reduction of inflammatory cells close the lesion site. A slight reduction of astrogliosis was also evident. Overall, the results obtained with the present work indicate that the cotransplantation of ASCs and OECs brings important functional benefits to the injured spinal cord. Stem Cells 2018;36:696-708.

Old and new challenges in Parkinson's disease therapeutics.

Parkinson's disease (PD) is a neurodegenerative disorder characterized by the degeneration of dopaminergic neurons and/or loss od neuronal projections, in several dopaminergic networks. Current treatments for idiopathic PD rely mainly on the use of pharmacologic agents to improve motor symptomatology of PD patients. Nevertheless, so far PD remains an incurable disease. Therefore, it is of utmost importance to establish new therapeutic strategies for PD treatment. Over the last 20 years, several molecular, gene and cell/stem-cell therapeutic approaches have been developed with the aim of counteracting or retarding PD progression. The scope of this review is to provide an overview of PD related therapies and major breakthroughs achieved within this field. In order to do so, this review will start by focusing on PD characterization and current treatment options covering thereafter molecular, gene and cell/stem cell-based therapies that are currently being studied in animal models of PD or have recently been tested in clinical trials. Among stem cell-based therapies, those using MSCs as possible disease modifying agents for PD therapy and, specifically, the MSCs secretome contribution to meet the clinical challenge of counteracting or retarding PD progression, will be more deeply explored.

Unveiling the Differences of Secretome of Human Bone Marrow Mesenchymal Stem Cells, Adipose Tissue-Derived Stem Cells, and Human Umbilical Cord Perivascular Cells: A Proteomic Analysis.

The use of human mesenchymal stem cells (hMSCs) has emerged as a possible therapeutic strategy for CNS-related conditions. Research in the last decade strongly suggests that MSC-mediated benefits are closely related with their secretome. Studies published in recent years have shown that the secretome of hMSCs isolated from different tissue sources may present significant variation. With this in mind, the present work performed a comparative proteomic-based analysis through mass spectrometry on the secretome of hMSCs derived from bone marrow (BMSCs), adipose tissue (ASCs), and human umbilical cord perivascular cells (HUCPVCs). The results revealed that BMSCs, ASCs, and HUCPVCs differed in their secretion of neurotrophic, neurogenic, axon guidance, axon growth, and neurodifferentiative proteins, as well as proteins with neuroprotective actions against oxidative stress, apoptosis, and excitotoxicity, which have been shown to be involved in several CNS disorder/injury processes. Although important changes were observed within the secretome of the cell populations that were analyzed, all cell populations shared the capability of secreting important neuroregulatory molecules. The difference in their secretion pattern may indicate that their secretome is specific to a condition of the CNS. Nevertheless, the confirmation that the secretome of MSCs isolated from different tissue sources is rich in neuroregulatory molecules represents an important asset not only for the development of future neuroregenerative strategies but also for their use as a therapeutic option for human clinical trials.

Mesenchymal stem cells secretome as a modulator of the neurogenic niche: basic insights and therapeutic opportunities.

Neural stem cells (NSCs) and mesenchymal stem cells (MSCs) share few characteristics apart from self-renewal and multipotency. In fact, the neurogenic and osteogenic stem cell niches derive from two distinct embryonary structures; while the later originates from the mesoderm, as all the connective tissues do, the first derives from the ectoderm. Therefore, it is highly unlikely that stem cells isolated from one niche could form terminally differentiated cells from the other. Additionally, these two niches are associated to tissues/systems (e.g., bone and central nervous system) that have markedly different needs and display diverse functions within the human body. Nevertheless they do share common features. For instance, the differentiation of both NSCs and MSCs is intimately associated with the bone morphogenetic protein family. Moreover, both NSCs and MSCs secrete a panel of common growth factors, such as nerve growth factor (NGF), glial derived neurotrophic factor (GDNF), and brain derived neurotrophic factor (BDNF), among others. But it is not the features they share but the interaction between them that seem most important, and worth exploring; namely, it has already been shown that there are mutually beneficially effects when these cell types are co-cultured in vitro. In fact the use of MSCs, and their secretome, become a strong candidate to be used as a therapeutic tool for CNS applications, namely by triggering the endogenous proliferation and differentiation of neural progenitors, among other mechanisms. Quite interestingly it was recently revealed that MSCs could be found in the human brain, in the vicinity of capillaries. In the present review we highlight how MSCs and NSCs in the neurogenic niches interact. Furthermore, we propose directions on this field and explore the future therapeutic possibilities that may arise from the combination/interaction of MSCs and NSCs.

The Secretome of Bone Marrow and Wharton Jelly Derived Mesenchymal Stem Cells Induces Differentiation and Neurite Outgrowth in SH-SY5Y Cells.

The goal of this study was to determine and compare the effects of the secretome of mesenchymal stem cells (MSCs) isolated from human bone-marrow (BMSCs) and the Wharton jelly surrounding the vein and arteries of the umbilical cord (human umbilical cord perivascular cells (HUCPVCs)) on the survival and differentiation of a human neuroblastoma cell line (SH-SY5Y). For this purpose, SH-SY5Y cells were differentiated with conditioned media (CM) from the MSCs populations referred above. Retinoic acid cultured cells were used as control for neuronal differentiated SH-SY5Y cells. SH-SY5Y cells viability assessment revealed that the secretome of BMSCs and HUCPVCs, in the form of CM, was able to induce their survival. Moreover, immunocytochemical experiments showed that CM from both MSCs was capable of inducing neuronal differentiation of SH-SY5Y cells. Finally, neurite lengths assessment and quantitative real-time reverse-transcription polymerase chain reaction (RT-PCR) analysis demonstrated that CM from BMSCs and HUCPVCs differently induced neurite outgrowth and mRNA levels of neuronal markers exhibited by SH-SY5Y cells. Overall, our results show that the secretome of both BMSCs and HUCPVCs was capable of supporting SH-SY5Y cells survival and promoting their differentiation towards a neuronal phenotype.

Interactions between Schwann and olfactory ensheathing cells with a starch/polycaprolactone scaffold aimed at spinal cord injury repair.

Spinal cord injury (SCI) represents a major world health problem. Therefore it is urgent to develop novel strategies that can specifically target it. We have previously shown that the implantation of starch-based scaffolds (SPCL) aimed for spine stabilization on SCI animals leads to motor skills improvements. Therefore, we hypothesize that the combination of these scaffolds with relevant cell populations for SCI repair will, most likely, lead to further improvements. Therefore, in this work, the ability of SPCL scaffolds to support the 3D culture of olfactory ensheathing cells (OECs) and Schwann cells (SCs) was studied and characterized. The results demonstrate for the first time that SPCL scaffolds were able to support the growth and migration of OECs and SCs. Moreover, the results indicate that two weeks of in vitro culture is the ideal time to reach a high number of transplantable cells. Future work will focus on the spine stabilization of SCI animals using SPCL scaffolds loaded with OECs or SCs for SCI regeneration.