Preclinical Comparison of Stem Cells Secretome and Levodopa Application in a 6-Hydroxydopamine Rat Model of Parkinson’s Disease

Abstract

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 per se appears to be a modulator of the dopaminergic system, enhancing TH-positive cells expression (e.g., dopaminergic neurons) and terminals both in the SN and STR when compared to the untreated group 6-OHDA. Such finding was positively correlated with a significant amelioration of the motor outcomes of 6-OHDA PD animals (assessed by the staircase test). Thus, the present findings support hBM-MSCs secretome administration as a potential therapeutic tool in treating PD, and although we suggest candidate molecules (Trx1, SEMA7A, UCHL1, PEDF, BDNF, Clusterin, SDF-1, CypA, CypB, Cys C, VEGF, DJ-1, Gal-1, GDNF, CDH2, IL-6, HSP27, PRDX1, UBE3A, MMP-2, and GDN) and possible mechanisms of hBM-MSCs secretome-mediated effects, further detailed studies are needed to carefully and clearly define which players may be responsible for its therapeutic actions. By doing so, it will be reasonable to presume that potential treatments that can, per se, or in combination modulate or slow PD may lead to a rational design of new therapeutic or adjuvant strategies for its functional modeling and repair.

Impact of Aging on the 6-OHDA-Induced Rat Model of Parkinson’s Disease

“…Contrarily to lesions in the SNpc and striatum, MFB lesions have the advantage of mimicking the late stage of PD [27]. Moreover, it avoids direct mechanical damage of the SNpc and striatum, allowing further screening studies, such as the injection of cell grafts, neuroprotective molecules, as wells as the cellular secretome into these brain regions [13,14,16,28].…”

Therapeutic utility of mesenchymal stromal cell (MSC)-based approaches in chronic neurodegeneration: a glimpse into underlying mechanisms, current status, and prospects

“…Moreover, it has been suggested that the antioxidant effect, which is elicited by MSC-derived secretome, could bring about by Sirt3 delivery, leading to substantial neuroprotective influences in vivo [ 156 ]. Other reports have also shown that desired effects induced by MSC-derived exosome therapy were largely mediated by various biologic molecules in MSC-derived secretome, including stromal cell-derived factor-1 (SDF-1 or CXCL12), growth factors (BDNF, VEGF and GDNF), MMP2, heat shock protein 27 (HSP27), and semaphorin 7a (sema7a) [ 157 ].…”

Stem Cell-Based Disease Modeling and Cell Therapy

“…Stem cell-derived secretome represents one promising therapeutic strategy. Teixeira et al found that BM-MSCs secretome resulted in a significant amelioration in the animal behavior in a Parkinson’s Disease rat model [ 30 ]. EVs are membrane-bound cellular products (30–1000 nm) that contain various classes of nucleic acids as well as soluble and transmembrane proteins.…”

“…This Special Issue includes both research [ 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 ] and reviews articles [ 10 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 ] which cover wide ranges of stem cell research: adult stem cells, cancer stem cells, pluripotent stem cells, and complex 3D organoid/cell aggregate models [ 26 , 27 , 33 ], with the focuses on stem cell biology/technology [ 10 , 23 , 24 , 25 , 26 , 31 , 32 , 34 ], and stem cell-based disease modeling [ 10 , 27 , 29 , 31 , 33 , 38 , 43 ] and cell therapy [ 24 , 28 , 30 , 32 , 35 , 36 , 37 , 39 , 40 , 41 ].…”

“…iPSCs can be generated from diverse patient populations, expanded, and differentiated into a disease-related specific cell types (e.g., neurons and cardiomyocytes) that can be either cultured as two-dimensional (2D) monolayers or included in stem cell-derived organoids, which can then be used as a tool to improve the understanding of disease mechanisms and to test therapeutic interventions [9,21,22]. This Special Issue includes both research [23][24][25][26][27][28][29][30][31][32] and reviews articles [10,[33][34][35][36][37][38][39][40][41][42] which cover wide ranges of stem cell research: adult stem cells, cancer stem cells, pluripotent stem cells, and complex 3D organoid/cell aggregate models [26,27,33], with the focuses on stem cell biology/technology [10,[23][24][25][26]31,32,34], and stem cell-based disease modeling [10,27,29,31,33,38,43] and cell therapy [24,28,…”