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Manipulated mesenchymal stem cell therapy in the treatment of Parkinson’s disease

Stem Cell Research & Therapy volume 15, Article number: 476 (2024) Cite this article

Abstract

Mesenchymal stem cell (MSC) therapy has been considered a promising approach for the treatment of Parkinson's disease (PD) for several years. PD is a globally prevalent neurodegenerative disease characterized by the accumulation of Lewy bodies and the loss of dopaminergic neurons, leading to severe motor and non-motor complications in patients. As current treatments are unable to halt the progression of neuronal loss and dopamine degradation, MSC therapy has emerged as a highly promising strategy for PD treatment. This promise is due to MSCs' unique properties compared to other types of stem cells, including self-renewal, differentiation potential, immune privilege, secretion of neurotrophic factors, ability to improve damaged tissue, modulation of the immune system, and lack of ethical concerns. MSCs have been employed in numerous pre-clinical and clinical studies for PD treatment with promising results. However, certain aspects of their efficacy in treating PD may benefit from various genetic and epigenetic modifications. In this review article, we assess these approaches to improving MSCs for specialized treatment of PD.

Background

Parkinson’s disease (PD) is a complex, age-related disorder that primarily affects individuals over the age of 65. It is characterized by the degeneration of dopaminergic neurons in the substantia nigra, leading to both motor and non-motor deficits due to decreased dopamine (DA) levels in the striatum [1,2,3]. Parkinson's disease (PD) is the second most prevalent neurodegenerative disorder after Alzheimer's disease (AD) and has the highest growth rate among all neurological diseases [4]. The molecular basis of neurodegeneration in PD has informed therapeutic strategies in recent years. However, current approaches mainly focus mainly on pharmacotherapy and symptom relief. Pharmacological treatments, such as levodopa, can cause unwanted side effects like dyskinesia, and they do not prevent the progression of PD. In contrast, cell therapies for PD aim to provide patients with long-term symptom relief and replace degenerated neurons [5]. Four types of stem cells have been investigated for the treatment of PD: mesenchymal stem cells (MSCs), neural stem cells (NSCs), induced pluripotent stem cells (iPSCs), and embryonic stem cells (ESCs) [6, 7]. Among these, MSCs offer distinct advantages due to their multipotentiality, immunomodulatory effect, self-renewal ability, migratory capacity, long-term survival, and the absence of ethical concerns. MSCs can be derived from various sources, including bone marrow, umbilical cord, placenta, adipose tissue, and dental pulp [8,9,10]. These cells express surface markers such as CD90 + , CD73 + and CD105 + , but they do not express CD14,CD11b, CD34, CD19, CD79a and HLA-DR [11]. The investigation of the therapeutic potential of MSCs in PD began in 2001 with Li and colleagues using a mouse model. Research has continued since then, producing promising results. However, MSC-based therapies for PD face several challenges, including the establishment of effective animal models that mimic human conditions, determining the optimal number of injections, optimizing administration routes, addressing heterogeneity, refining isolation and production techniques, and mitigating the negative impact of a high number of cell passages on MSC self-renewal and multipotent activities. Safety concerns also remain. Genetic modification of MSCs may help to overcome these obstacles and personalize the therapy to a greater extent [12]. The aim of this literature review is to provide insight into the use of manipulated MSCs in the treatment of PD (Fig. 1).

Fig. 1
figure 1

Therapeutic effects of mesenchymal stem cells (MSCs) in the treatment of Parkinson’s disease (PD). MSCs secrete trophic factors and cytokines that help in the repair and regeneration of tissue. They also regulate the immune system by interacting with immune cells and modulating anti-inflammatory effects, and they promote neurogenesis that contributes to the functional recovery of lost neurons without ethical concerns and tumorigenic aspects in PD patients

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Brief overview of preclinical studies on MSC therapy for PD

In 2001, Li et al. used bone marrow-derived mesenchymal stem cells (BMSCs) from adult male C57BL/6 mice to treat the MTPT (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) model of PD. The BMSCs were administered by stereotactic surgery into the striatum of the mice. One month after transplantation, these cells exhibited tyrosine hydroxylase (TH) immunoreactivity, and behavioral improvement along with neurological recovery were observed [13]. In 2004, Dewaza et al. employed rat and human BMSCs differentiated into functional dopaminergic neurons through the transfection of the Notch intracellular domain (NICD) gene and treatment with trophic factors such as basic fibroblast growth factor (bFGF), forskolin, and ciliary neurotrophic factor. These were administered via the intrastriatal route in a 6-hydroxy-dopamine (6-OHDA) rat model of PD, resulting in improvements in motor behavior [14]. Kim et al. observed that the therapeutic effect of MSCs was due to the anti-inflammatory cytokines within the secretome. This study demonstrated the protective effect of human bone marrow-derived mesenchymal stem cells (hBMSCs) on the dopaminergic system by employing anti-inflammatory pathways, including the reduction of microglial activation and the downregulation of tumor necrosis factor (TNF-α) and inducible nitric oxide synthase (iNOS) mRNA expression in both in vivo and in vitro models [15]. Blandini and colleagues tested the intrastriatal injection of human MSC in a 6-OHDA animal model. Post-transplantation, the MSCs survived, integrated into the lesion region, reduced damage, and a therapeutic effect was observed [16]. Ahmed et al. demonstrated that intravenous (IV) administration of rat BMSCs in the rotenone animal model of PD resulted in an increase in nestin gene expression, as well as elevated brain TH and DA levels[17]. Salama et al. used intranasal (IN) administration of mourinic micrometer-sized iron oxide (MPIO)-labeled MSCs in a rat model created by intraperitoneal (IP) administration of rotenone. The neurobehavioral assessment showed improvements in the treatment group, and positive Prussian blue staining indicated that the MSCs were successfully delivered to the brain, reducing the degeneration of dopaminergic neurons [18]. In the study by Schwerk and colleagues involving the 6-OHDA animal model, adipose-derived mesenchymal stem cells (AD-MSCs) were transplanted into the substantia nigra of rats. Three days post-transplantation, most MSCs were localized in the substantia nigra area and surrounding arachnoid, and a significant increase in subventricular neurogenesis was observed in MSC-transplanted animals compared to non-transplanted animals [19]. According to experiments conducted by Forouzandeh et al., human conjunctiva-derived MSCs (CJ-MSCs) exhibited a protective effect against PD and enhanced the ability of nerves to express DA, leading to improved behavioral outcomes [20]. In a study by McCoy and colleagues, autologous transplantation of naïve and differentiated adipose-derived MSCs one week after 6-OHDA injection in female rats resulted in less loss of TH immunoreactivity, reduced microglial activation, and improved locomotor function due to the production of trophic factors at the lesion site [21].

Brief overview of clinical trials of MSC therapy in the treatment of PD

In 2010, Venkataramana conducted a research project in India that tested stem cell therapy for PD through the unilateral transplantation of the patient's own bone marrow cells directly into the sublateral ventricular zone of the brain. Out of seven patients, three exhibited progress in movement, as assessed by the Unified PD Rating Scale (UPDRS), the Schwab and England (S&E) scale, and the Hoehn and Yahr (H&Y) scale during a follow-up period of 10 to 36 months. Additionally, two patients significantly reduced L-DOPA doses. The treatment appeared to be safe, with no major complications reported throughout the procedure [22]. In 2011, Qiu et al. administered human umbilical cord-derived MSCs (hUC-MSCs) via carotid artery injection to eight patients—four men and four women—diagnosed with PD. One month after the treatment, the patients demonstrated a regression in UPDRS scores, indicating improvements in symptoms such as tremor and rigidity. No side effects were observed in this study [23]. In 2014, Wang et al. conducted a transplantation of hUC-MSC in 15 PD patients. The study noted symptom relief and the absence of major side effects one month post-transplantation, suggesting a potential benefit of stem cell therapy [24]. In 2016, Canesi et al. explored the efficacy of MSC therapy in treating progressive supranuclear palsy (PSP), a variant of Parkinsonism with currently no effective therapeutic interventions. Five patients received MSCs derived from bone marrow, administered into the cerebral arteries. All patients, except one who died from a fall, either remained stable or showed improvements in motor functions such as movement and balance [25]. Also in 2016, a limited study administered allogeneic hUC-MSCs intravenously to five PD patients. This resulted in clinical improvement in UPDRS scores in three patients within three months [26]. In 2020, Boika and colleagues enrolled 12 PD patients in a limited study where autologous bone marrow-derived MSCs were administered intravenously and intranasally. Significant improvements in both motor and non-motor symptoms were observed at one and three months post-treatment [27]. In 2021, Schiess et al. assessed the safety and potential benefits of allogeneic hBMSCs in 20 PD participants. The study confirmed the benefit of allogeneic mesenchymal stem cells based on the UPDRS results at the one-year follow-up period after cell therapy [28]. In early 2022, Shigematsu et al. repeated the infusion of autologous adipose-derived stem cells (ADSCs) five or six times intravenously in three PD patients. Over the six -month observation period, no adverse side effects were reported, and all participants showed improvements in their movements [29] (Fig. 2).

Fig. 2
figure 2

Preclinical and clinical studies on mesenchymal stem cells (MSCs) therapy for Parkinson’s disease (PD). Various preclinical and clinical studies have investigated the safety and efficacy of MSC therapy. MSCs have been isolated from various sources such as bone marrow, umbilical cord, adipose tissue and conjunctiva and administered via different routes of administration such as intrastriatal (IS), intranasal (IN) and intravenous (IV) in animal models of PD and the sublateral ventricular zone (SVZ), intra-arterial (IA), intravenous (IV) and intranasal (IN) in PD patients

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PD-related transcription factors as a promising therapeutic strategy

Understanding the complex molecular factors associated with PD provides researchers with precise clues and new insights into manipulating MSCs, especially at the epigenetic and genetic levels, to generate dopaminergic neurons and slow disease progression. In 2022, Raghavan reported that human dermal fibroblasts treated with Metadichol, a non-toxic nanoemulsion of long-chain lipid alcohols, in their culture media showed asignificant increase in the expression of various transcription factors. These factors included achaete-scute bHLH transcription factor 1 (ASCL1), forkhead box A2 (FOXA2), pituitary homeobox 3 (PITX3), and LIM homeobox transcription factor 1 alpha (LMX1A), all of which are involved in the generation of dopaminergic neurons [30].

In a recent study by Al-Nusaif, the role of nuclear receptor-related factor 1 (NURR1) in dopaminergic neuron development was emphasized. NURR1 is known to regulate the expression of key genes involved in dopamine synthesis and storage, including tyrosine hydroxylase (TH) and vesicular monoamine transporter 2 (VMAT2) [31]. Paired-like homeodomain transcription factor 3 (Pitx3) is also crucial for the development of midbrain dopaminergic neurons and plays an essential role in their terminal differentiation and maintenance during both embryonic and postnatal stages. Variants of the Pitx3 gene have been linked to sporadic and early-onset Parkinson's disease. Studies have shown that Pitx3 expression is significantly reduced in peripheral blood lymphocytes and brain tissue of PD patients compared to controls [32]. Additionally, a study by Oh et al. demonstrated that the injection of adeno-associated virus (AAV) vectors carrying the genes for NURR1 and FOXA2 into the substantia nigra (SN) of a PD mouse model revealed that these two factors collaborate to enhance dopaminergic neuron survival. NURR1 functions as a transcription factor regulating gene expression, while FOXA2 acts as a co-activator, amplifying the effects of NURR1. This synergy is critical for the proper functioning of dopaminergic neurons [33].

The protein P53 also plays a significant role in PD pathogenesis. Research suggests that p53 is activated in response to cellular stressors associated with PD, including mitochondrial dysfunction and oxidative stress. Elevated levels of p53 and apoptosis-related proteins, such as BAX, have been observed in the brains of PD patients, suggesting that p53 may contribute to neuronal cell death. Targeting p53 therapeutically could help reduce neuronal loss in PD [34]. A study by Price et al. revealed that the transcription factor DLX1 interacts significantly with components of the nucleosome remodeling and deacetylase (NuRD) complex, particularly RBBP4 and RBBP7. This interaction influences chromatin remodeling and gene repression. DLX1 regulates genes associated with neurogenesis and neuronal survival and is involved in cellular responses to oxidative stress. Thus, changes in DLX1 expression may affect dopaminergic neuron survival, while the role of NuRD's role in epigenetic regulation could impact neurodegeneration progression in PD [35]. Kruppel-like transcription factor 7 (KLF7) is also essential for proper neuronal development, especially in regions such as the olfactory and visual systems, the cerebral cortex, and the hippocampus. KLF7 promotes the transcription of cyclin-dependent kinase inhibitors, which are vital for neuronal differentiation and morphogenesis. This regulation supports neuronal health and development, potentially impacting conditions like PD [36]. Optimizing MSC function based on these transcription factors may offer a novel pathway for therapeutic interventions.

Manipulation of MSCs with growth factors, biological agents, hypoxia, and genetic engineering

Manipulation and pre-activation of MSCs are strategic approaches designed to address the challenges encountered in stem cell therapy, such as poor transplantation outcomes, low survival rates, and limited efficacy under various host conditions, including age, disease, and immune response. These pre-activation strategies aim to enhance the function, viability, efficacy, and disease specificity of MSCs post-transplantation, thereby reducing health risks and associated costs [37]. MSCs can be genetically and epigenetically modified using a variety of chemical, physical, and biological agents or through specific conditions to improve their efficacy and safety [38]. Primed MSCs can be used in different kind of disease including neurodegenerative, autoimmune, inflammatory, skin, respiratory, neuromuscular and hematological diseases [39].

Priming MSCs with growth factors and cytokines has been demonstrated to enhance the healing of injury and disease, promote angiogenesis and blood vessel formation, and improve the overall biological function of MSCs [40]. For instance, growth factors such as fibroblast growth factor-2 (FGF-2) have been shown to regulate the expression of cytokines and chemokines in human dental pulp-derived MSCs, thus influencing their regenerative and therapeutic potential [41]. In another study, FGF-2 played a significant role in priming MSCs for chondrogenesis [42]. The pre-conditioning of MSCs with TGF-α resulted in improved post-ischemic myocardial function, with a decrease in the production of inflammatory cytokines, leading to better recovery following injury [43]. Pre-treatment of MSCs with growth factors such as FGF-2, bone morphogenetic protein-2 (BMP-2), and insulin-like growth factor-1 (IGF-1) enhanced the expression of cardiac transcription factors, including GATA-4 and NKx-2.5, promoting cardiomyogenic differentiation and leading to improved therapeutic outcomes in myocardial injury [44]. Simultaneous injection of MSCs with vascular endothelial growth factor (VEGF) reduced cellular stress markers in MSCs and promoted growth and survival in infarcted hearts [45]. Pre-activation of MSCs with stromal-derived factor-1 (SDF-1) increased VEGF secretion, a crucial factor in angiogenesis [46]. Keratinocyte growth factor (KGF) played a critical role in mediating the protective effects of cryopreserved xenogeneic-free human MSCs when pre-activated with cytokines such as interleukin (IL)-1β, TNF-α, and interferon (IFN)-γ, potentially aiding in the healing of injuries such as ventilator-induced lung injury (VILI) [47].

Herbal extracts and biological compounds like vitamin E and curcumin enhance the resistance of MSCs to oxidative stress and support tissue repair, thereby improving their therapeutic potential in wound healing and ischemic diseases [37]. Adipose-derived mesenchymal stem cells (ADSCs) pre-treated with curcumin, an extract of turmeric, exhibited increased viability, VEGF secretion, and survival after transplantation into a rat myocardial infarction model, resulting in improved cardiac function, reduced infarct size, and lower myocardial apoptosis [48]. Pre-treatment of MSCs with curcumin loaded in nanospheres significantly enhanced their migration during the wound healing process [49]. The survival of olfactory mucosa-derived MSCs (OM-MSCs) was improved by curcumin pre-treatment, as evidenced by the reduction of adenosine triphosphate (ATP), reactive oxygen species (ROS), malonaldehyde (MDA), and lipid hydroperoxide (LPO) [50]. Pre-treatment of MSCs with vitamin E increased resistance to H2O2-induced oxidative stress and expression of transforming growth factor-beta (TGF-β). Transplantation of these vitamin E-pretreated MSCs resulted in increased proteoglycan content in the cartilage matrix in a rat model of osteoarthritis (OA) [51]. Pre-conditioning of MSCs with bioactive compounds such as quercetin and rutin from Melia azedarach improved their survival and regenerative potential, and the transplantation of these cells into a rat cold burn wound model resulted in enhanced skin regeneration, neovascularization, and wound healing [52]. MSCs treated with melatonin showed increased survival and recovery of renal function after injection into the kidney of a rat model of acute renal failure [53].

The natural niches of endogenous MSCs are characterized by lower oxygen levels(1–7%), in contrast to the oxygen-rich conditions found in in vitro cell culture environments (21%) [54, 55]. Hypoxic pre-activation maintains MSCs in an undifferentiated state, preserving their stem cell properties, promoting gene stability, and enhancing paracrine function, proliferation, survival, migration, and homing ability, as well as reducing DNA damage, thereby making them more effective in therapeutic applications [56, 57]. Hypoxia can lead to epigenetic modification, such as changes in DNA methylation and hydroxymethylation patterns, which can affect gene expression and the functional properties of MSCs [58, 59]. Hypoxia-preconditioned MSCs have demonstrated therapeutic benefits for kidney tissue repair in a porcine model of atherosclerotic renal artery stenosis (ARAS) [58]. Hypoxic preconditioning enhanced the adaptability of MSCs to tissue environments and preserved their immunomodulatory and regenerative properties for medical uses [60]. Pre-culturing MSCs under low oxygen conditions increased the secretion of hepatocyte growth factor (HGF), and other growth factors like VEGF and basic fibroblast growth factor (bFGF), enhancing their proliferation, survival, and osteogenic and adipogenic differentiation potentials [61]. Hypoxic preconditioning of MSCs enhanced the expression of cMet, the primary receptor for HGF, enabling HGF expressed at the injury site to serve as a chemotactic factor that attracts injected MSCs from the bloodstream to the damaged tissue. This process promotes tissue repair and revascularization in a murine hind limb ischemia model [62]. Infusion of hypoxia-preconditioned MSCs significantly increasedhepatocyte proliferation markers, the liver weight/body weight ratio, and survival rates compared to normoxia-preconditioned MSCs [63]. Hypoxic pre-culturing MSCs transplanted into a rat model of myocardial infarction (MI) improved survival rates, angiogenesis, and heart function [64].

Genetic engineering of MSCs involves modification their genetic material to enhance their therapeutic potential, using both viral and non-viral methods [65]. Viral vectors used for MSCs manipulation include lentiviruses, retroviruses, adenoviruses, and adeno-associated viruses, while non- viral methods include electroporation, nucleofection, lipid polymeric agents, dendrimers, and inorganic nanoparticles [66]. Gene-modified MSCs that overexpressed adhesion molecules like E-selectin using a safe and approved vector, such as adeno-associated virus (AAV), accelerated wound healing and enhanced angiogenesis in murine model of hindlimb ischemia [67]. MSCs engineered to express growth factors showed increased production and secretion of these factors, thereby boosting their regenerative potential [66]. For example, MSCs genetically altered to express human bone morphogenetic protein-2 (hBMP-2) led to bone regeneration and repair [68]. Angiogenin-modified MSCs demonstrated significantly higher survival rates under hypoxic conditions, leading to improved viability in a rat model of acute myocardial infarction [69]. Transplantation of MSCs genetically modified to express multineurotrophin MNTS1 resulted in neuronal survival and axonal growth [70].

Epigenetically manipulated MSCs therapy in the treatment of PD

In 2024, Zhou et al. investigated the safety and efficacy of hypoxia-preconditioned human olfactory mucosa mesenchymal stem cells (hOM-MSCs) in patients with PD. The study involved 5 volunteers aged 50 to 80 years, diagnosed with PD for more than 5 years and with a Hoehn and Yahr grade of 3 or higher. Participants received an intrathecal injection of autologous hOM-MSCs derived from their olfactory mucosa. The study reported improvements in motor function, mood, and daily activities, along with a significant reduction in the required oral maintenance dose of levodopa, and no serious adverse events were noted during follow-up. In addition, CSF and serum analyses indicated increased levels of dopamine, TGF-β1, IL-4 and IL-10, and a decrease in TNF-α and IL-1β [71].

In another part of this study, hOM-MSCs were transplanted into MPTP-induced PD mouse models via stereotactic injection into the lateral ventricle. Results showed significant improvements in motor functions and reduced neurological damage in these models [71]. In 2022, Shin et al. stimulated MSCs with α-synuclein, which increased their stemness capacity by upregulating transcription factors such as NANOG, octamer-binding transcription factor 4 (OCT4), Kruppellike factor 4 (KLF4), and neurogenic locus notch homolog protein (Notch). This stimulation also enhanced autophagy-regulating microRNAs (miRNAs), which are critical for cellular health and function, particularly in the context of neurodegenerative diseases like PD. MSCs treated with α-synuclein showed increased neuronal viability and elevated autophagy markers, including BECN1-regulated autophagy protein 1 (AMBRA1), in an α-synuclein overexpressing Parkinsonian cellular model (SH-SY5Y cells), compared to naïve MSCs. Injecting α-synuclein-primed MSCs into α-synuclein-overexpressing PD mouse models, demonstrated a significant protective effect on dopaminergic neurons [72].

In 2021, Kim et al. primed MSCs with uric acid (UA) and injected them via the tail vein into the MPTP-induced PD mouse model. Results indicated that UA-primed MSCs significantly reduced cleaved caspase-3 expression, thereby decreasing apoptosis in dopaminergic neurons. The treatment also affected key transcription factors and microRNAs, leading to improved motor recovery. Additionally, inflammatory responses were modulated, with a reduction in pro-inflammatory cytokines and an increase in anti-inflammatory cytokines, compared to naïve MSCs [73]. In 2020, Singh et al. demonstrated that forskolin, particularly when combined with FGF2, can induce hMSCs to differentiate into dopaminergic neurons. The highest upregulation of dopaminergic markers was observed in adipose tissue-derived MSCs (AD-MSCs), followed by bone marrow-derived MSCs (BM-MSCs) and dental pulp-derived MSCs (DP-MSCs), indicating a promising approach for PD treatment [74]. In 2019, Wang and colleagues isolated and expanded hUC-MSCs, activating these stem cells using different concentrations of curcumin. They evaluated the effects of hUC-MSCs-CUR transplantation into the MPTP-induced PD mouse models via the tail vein on motor ability, TH, DA, and apoptosis-related protein expression, with progressive improvements reported [75]. Chung et al. demonstrated that dextran-coated iron oxide nanoparticles (Dex-IO NPs) enhanced the therapeutic effect of human MSCs (hMSCs) in the 6-OHDA model of PD. This was achieved by improving the migration capacity of hMSCs towards damaged dopaminergic neurons and promoting their differentiation into dopamine-like neurons. The nanoparticles induced the expression of migration-guided receptors, such as the epidermal growth factor receptor (EGFR), CXCR4 and IL-15R, facilitating movement toward the lesion, which resulted in improvements in behavioral tests and recovery process. This study highlighted the value of manipulating of MSCs to enhance therapeutic efficacy [76]. In 2016, Jinfeng et al. examined the therapeutic effect of the supernatant of hUC-MSCs treated with curcumin (CUR) on PC12 cells, a PD cell model induced by 1-methyl-4-phenylpyridinium ion (MPP +). The results showed promise in improving proliferation, apoptosis, neuronal differentiation, and antioxidative ability [77]. In 2015, Zhao et al. induced differentiation of hUC-MSCs into dopaminergic-like neurons using culture media containing DMEM/F12 supplemented with L-ascorbic acid, fibroblast growth factor (FGF), sonic hedgehog (Shh), bFGF and N2. Transplantation of these DAergic-like neurons into the striatum of the 6-OHDA rat model of PD resulted in improved behavioral assessments and a significant increase in heat shock protein 60 (Hsp60), suggesting a role in behavioral recovery [78]. In 2013, Shetty and colleagues successfully differentiated MSCs isolated from bone marrow and the umbilical cord into a dopaminergic phenotype using a two-step protocol. In the first step, medium consisting of DMEM/F12, 10% serum, basic fibroblast growth factor, B27, nerve growth factor, and Noggin was used for one week. In the next step, the same medium was supplemented with BHA for 24 h. The analysis showed increased expression of TH and Nurr1, indicated successful differentiation. Transplantation of these differentiated MSCs into the substantia nigra led to improved behavioral tests compared to the control group [79]. In 2011, Khoo et al. investigated three growth factor-based methods to induce neuronal differentiation in human MSCs: Single-step neuronal differentiation (SingleND), Multi-step dopaminergic neuronal differentiation (MultiDA) and Single-step dopaminergic neuronal differentiation (SingleDA). The hMSCs exhibited a neuron-like phenotype in vitro. However, their transplantation into a rat model of PD resulted in transient survival without differentiation into neuronal cells, as they did not express neuronal markers such as neuronal beta-tubulin III or TH at the transplantation sites. Further experiments are needed to improve the differentiation and survival of the transplanted cells in vivo [80]. In 2010, Somoza et al. used four different culture media to induce brain-derived neurotrophic factor (BDNF) expression in bone marrow mesenchymal stem cells isolated from humans, including serum-containing medium (MSC-medium), serum-free medium (NSC-medium), and their corresponding media supplemented with basic fibroblast growth factor (bFGF) and epidermal growth factor (EGF). Analysis showed that the supplementation of basic fibroblast growth factor (bFGF) and epidermal growth factor (EGF) to the serum-free medium (NSC-medium) induced higher BDNF release in hMSC cultures. Implantation of BDNF-secreting hMSC (hM(N)SC) into the substantia nigra of 6-OHDA rat model of PD was hopeful and indicated significant hypertrophy of nigral TH cells, increased striatal TH-staining, and amelioration of motor symptoms [81]. In 2010, Ming Li et al. used a two-step differentiation protocol for human umbilical vein-derived mesenchymal stem cells (hUV-MSCs) to differentiate into dopaminergic-like cells. First, hUV-MSCs were cultured in serum-free medium (DMEM/F12) containing epidermal growth factor (EGF), basic fibroblast growth factor (bFGF), and N2 to generate neural stem cell-like structures. In the second step, the stem cells were cultured in a medium enriched with DMEM/F12, BDNF, DA, and forskolin to transform the neurospheres into dopaminergic-like cells. These cells were transplanted into the brains of Parkinson's rats, showing partial improvement in motor function [82]. In 2009, Shetty et al. successfully transdifferentiated BMSCs into functional dopaminergic neurons under xenofree conditions. Xenofree conditions eliminate components such as fetal bovine serum (FBS) to minimize the risk of pathogen transmission to humans and ensure safety for clinical usage [83]. In 2009, Sadan et al. used a special protocol to induce hMSC into neurotrophic factor-secreting cells (NTF-SC). In the first step, MSCs were co-cultured with specific growth factors such as fibroblast growth factor (FGF), epidermal growth factor (EGF), and N2 supplement for 72 h. In the second step, other supplements such as cyclic AMP (dbcAMP), Isobutylmethylxanthine (IBMX), platelet-derived growth factor (PDGF), neuregulin 1-b1HRG1-b1 EGF domain, and hbFGF were added to the medium for another 72 h. The MSCs produced NTF-SC, which showed therapeutic potential in the 6-OHDA rat model of PD, compared to the implantation of human MSCs grown under serum-free conditions during the same time period [84]. Barzilay and colleagues in 2007 added various agents to the basic medium, including sonic hedgehog (Shh), fibroblast growth factor-8 (FGF8), transforming growth factor- 3 (TGFb3), glial-derived neurotrophic factor (GDFN), BDNF, Neurturin, neurotrophin-3 (NT3), and estrogen with and without retinoic acid (RA), in multiple combinations protocols to drive human MSCs towards dopaminergic cells. The results showed that a combination of Glial cell line-Derived Neurotrophic Factor (GDNF), Transforming Growth Factor-3 (TGF-3), and Retinoic Acid (RA) induced the highest level of TH expression [85]. Wang and colleagues demonstrated that hypoxic conditions (3% O2) in rat MSC cultures increased proliferation by upregulating the mitogen-activated protein kinase (p38 MAPK) signaling pathway and inducing the nuclear translocation of hypoxia-inducible factor (HIF)-1a, key factors for cell proliferation, and the promotion ofdopaminergic neuronal differentiation. In addition, hypoxia-induced dopaminergic neurons from human fetal MSCs transplanted into the 6-OHDA rat model of PD resulted in better behavioral assessment and survival of dopaminergic neurons [86]. (Table 1).

Table 1 The summary of epigenetically manipulated and co-transplanted mesenchymal stem cells (MSCs) therapeutic effect in the treatment of Parkinson’s disease (PD)
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Genetically manipulated MSC in the treatment of PD

In 2022, Jiang et al. genetically modified hUC-MSCs to express BDNF, aiming to enhance their therapeutic potential. The genetically modified hUC-MSCs were induced to differentiate into dopaminergic-like neurons, with the expression of neuronal markers such as nuclear receptor-related factor 1 (Nurr1) and TH confirmed. These modified stem cells were then transplanted into the 6-OHDA rat model of PD. The results demonstrated an increase in DA concentration in the striatum and substantia nigra, along with neuroprotective effects and an improved motor function [87]. Similarly, in 2022, Li et al. utilized lentiviral vectors to modify hUC-MSCs to synthesize three critical genes involved in DA production: TH, GTP cyclohydrolase 1 (GCH1), and aromatic amino acid decarboxylase (AADC). TH catalyzes the conversion of L-DOPA from the amino acid tyrosine, AADC converts L-DOPA to DA, and GCH1 produces tetrahydrobiopterin, a cofactor for the TH enzyme. When these DOPA-MSCs were transplanted into Sprague–Dawley rat and rhesus monkey models of PD, an increase in DA levels in the striatum was observed, along with long-term improvements in motor skills and symptoms [88]. In 2019, Lee et al. modified umbilical cord blood mesenchymal stem cells (UCB-MSCs) to secrete a soluble form of the receptor for advanced glycation end products (RAGE), which is involved in cell signaling. RAGE can bind to various molecules, such as advanced glycation end products (AGE) and S100 proteins, potentially leading to cell death (apoptosis) when these molecules bind to RAGE on cells. In the context of PD, the binding of AGE-albumin to RAGE is associated with neuronal death. By inhibiting this binding with sRAGE, neuronal cell death can be reduced. The sRAGE-secreting UCB-MSCs, generated using CRISPR/Cas9 technology and transplanted into the striatum of rotenone-induced PD animal models, showed efficacy in protecting neuronal cells and improving movement [89]. In 2018, Wang et al. cultured rat BMSCs and transfected them with the Nurr1 gene using a lentiviral vector. Nurr1, is a transcription factor belonging to the orphan nuclear receptor family, is responsible for the development, maturation, and protection of DA neurons in the striatum by regulating key proteins involved in DA production, such as TH, dopamine transporter (DAT), vesicular monoamine transporter (VMAT2), and AADC. Transplantation of these Nurr1-modified MSCs into the 6-OHDA model of PD resulted in decrease inflammation, increase dopaminergic neurons, and demonstrated therapeutic potential in the treatment of PD [90]. In 2015, Jinfeng Li et al. showed that human hUC-MSCs transduced with fibroblast growth factor-20 (FGF-20) via adenoviral vectors increased the expression of TH and DA levels in the substantia nigra of the PD mouse model, leading to an improvement in motor behavior [91]. Earlier, in 2014, Jiaming and Niu genetically modified rat BMSCs to express cerebral dopamine neurotrophic factor (CDNF), a protein that can protect dopaminergic neurons from degeneration. These CDNF-expressing MSCs were administered in three different ways—intra-striatal, intraventricular and, intravenous—in a rat model of PD. The intra-striatal transplantation of CDNF-MSCs proved most effective, showing significant improvements in behavioral assessments compared to other routes [92]. Also in 2014, Yin and colleagues transduced persephin (PSPN) gene into the genome of rat BMSCs using adenoviruses. Persephin, a neurotrophic factor belonging to the glial cell line-derived neurotrophic factor (GDNF) family, was expressed in modified MSCs (Lv-PSPN-MSCs). When administered into the striatum in the 6-OHDA rat model of PD, these cells showed improved behavioral assessments and increased DA levels compared to control MSCs, confirming the supportive effect of PSPN expression in MSCs for treating PD [93]. In another study by Jinfeng Li et al. in 2013, hUC-MSCs were successfully transduced with the hepatocyte growth factor (HGF) gene. The continuous production of HGF by these MSCs led to their differentiation into dopaminergic neuron-like cells capable of producing DA, TH [94]. In 2011, Xiong et al. used adenovirus-mediated gene transfer to modify hUC-MSCs to express vascular endothelial growth factor (VEGF). Theses VEGF-expressing HUMSCs demonstrated efficacy in promoting behavioral recovery and protection of dopaminergic neurons in the rat model of rotenone-induced PD [95]. The same year, Shi et al. genetically modified rat BMSCs using lentiviral vectors to express both TH and GDNF. They investigated the synergistic effects of co-expressing TH and GDNF in MSCs, comparing it to the effects of expressing either TH or GDNF alone. The results revealed that the DA concentration in the striatum was higher in parkinsonian rats injected with TH/GDNF-expressing MSCs compared to those injected with MSCs expressing only TH or GDNF. Additionally, the co-expressing MSCs led to greater behavioral improvements [96]. In 2010, Glavaski et al. examined the implantation of hBMSCs that were genetically induced to secrete GDNF into the striatum of a rat model of PD. GDNF, a known supportive factor for dopaminergic neurons, showed promising results in improving motor function [97]. In 2009, Wu et al. generated BMSCs expressing GDNF using lentiviral vectors and investigated the therapeutic potential in a PD rat model induced by a lactacystin lesioning of the median forebrain bundles. The results indicated that the increase in TH and DA levels in the striatum led to behavioral recovery [98]. Earlier still, in 2006, Min Ye et al. studied three groups of rats with 6-OHDA lesions that were administered BMSCs transfected with the neurturin (NTN) gene, non-transfected BMSCs, or phosphate buffer saline (PBS) into the right striatum. Neurturin, a neurotrophic factor that promotes the survival and maintenance of dopaminergic neurons in the substantia nigra, was expressed in the BMSCs. The results showed that the expression of NTN in BMSCs led to increased DA levels in the striatum and improved behavioral tests compared to controls, indicating its therapeutic potential in PD [99]. Finally, in 2005, Lu et al. isolated and cultured MSCs from the bone marrow of rats and genetically engineered them using an adeno-associated virus (AAV) vector to express the TH gene. The injection of TH-expressing MSCs, compared to LacZ-expressing MSCs, resulted in increased DA levels in the striatum of parkinsonian rats and led to improvements in behavioral analysis [100]. (Table 2) (Fig. 3).

Table 2 The summary of genetically manipulated mesenchymal stem cells (MSCs) therapeutic effect in the treatment of Parkinson’s disease (PD)
Full size table
Fig. 3
figure 3

Manipulation of mesenchymal stem cells (MSCs) in the treatment of Parkinson’s disease (PD). Various approaches, especially genetic and epigenetic manipulation of MSCs, have been investigated for the treatment of PD. Genetic manipulation by transduction of various genes and epigenetic manipulation by co-culturing with biological agents such as curcumin and various growth factors or hypoxic conditions improve their functions, efficacy and safety of transplantation and their therapeutic properties in the treatment of PD

Full size image

Co-transplantation of MSC in the treatment of PD

Pereira et al. induced an experimental PD model using intranasal administration of the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). One week later, they administered hUC-MSC and a mixture of 50% UC-MSC and 50% fibroblasts into the right striatum of rats to assess the importance of cell purity in treatment. Although the therapeutic effects were observed with UC-MSC transplantation without the mixture of fibroblasts, contamination of MSC preparations with fibroblasts resulted in negative outcomes and abolished the neuroprotective effects of stem cell transplantation in rats [101]. Xiong and his team explored the effects of basic fibroblast growth factor (b-FGF) on hBMSCs both in vitro and in vivo. The addition of b-FGF was co-cultured with hBMSCs for 48 h at varying dose (10, 20, 50 and 100 ng/ml) and the MTT assay showed a significant increase in cell proliferation and viability. In the in vivo portion of the study, the effect of co-transplantation of hBMSCs with b-FGF as a therapy for rotenone-induced PD rat model was also investigated. The results demonstrated that hBMSCs promoted neurodifferentiation and decreased the number of rotations in behavioral assessments [102]. In 2011, Khoo et al. co-transplanted hMSCs with olfactory ensheathing cells (OECs) into hemiparkinsonian rat models to determine whether co-transplantation could enhance the engraftment and differentiation of hMSCs in a neurological environment. The results indicated that co-transplantation did not improve the survival or differentiation of hMSCs. Furthermore, the transplantation sites in the PD model exhibited an inflammatory response, similar to models with spinal cord injury [80]. In 2010, Ming Li et al. investigated the effects of administering nerve growth factor (NGF) alongside the transplantation of human umbilical vein-derived mesenchymal stem cell (hUV-MSC) dopaminergic-like cells into the striatum of rats. The study focused on DA levels and motor functions. The results revealed that NGF administration significantly improved the survival of the transplanted cells, increased the DA content in local brain tissue, and led to a more significant improvement in motor function compared to cell transplantation [82].

Conclusion

MSCs hold significant promise as a form of regenerative medicine due to their unique properties, including the secretion of trophic factors, modulation of immune system, enhancement of damage tissues, and the lack of ethical concerns. However, several challenges remain, such as low survival rates after transplantation, poor engraftment, and limited growth kinetics. Therefore, manipulating MSCs in various ways is crucial to overcome this obstacles, bringing the clinical application of MSCs closer to reality, particularly in the treatment of PD as a growing neurodegenerative condition that impose a significant burden on both patients and also society.

Data availability

Not applicable.

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Acknowledgements

The authors thank the Vice President of the Research Council of Mashhad University of Medical Sciences. This article is extracted from information from a master's thesis study (Code No. 4011885) / "The authors declare that they have not use AI-generated work in this manuscript".

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Authors and Affiliations

  1. Department of Immunology, Semnan University of Medical Sciences, Semnan, Iran

    Seyedeh Toktam Ekrani & Dariush Haghmorad

  2. Cancer Research Center, Semnan University of Medical Sciences, Semnan, Iran

    Seyedeh Toktam Ekrani & Dariush Haghmorad

  3. Immunology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran

    Mahmoud Mahmoudi & Seyed-Alireza Esmaeili

  4. Immunology Department, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran

    Mahmoud Mahmoudi & Seyed-Alireza Esmaeili

  5. Medical Laboratory Science Department, College of Science, University of Raparin, Rania, Sulaymaniyah, Iraq

    Ramiar Kamal Kheder

  6. Department of Medical Analysis, Faculty of Applied Science, Tishk International University, Erbil, Iraq

    Ramiar Kamal Kheder

  7. Department of Nutrition, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran

    Alireza Hatami

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Ekrani, S.T., Mahmoudi, M., Haghmorad, D. et al. Manipulated mesenchymal stem cell therapy in the treatment of Parkinson’s disease. Stem Cell Res Ther 15, 476 (2024). https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s13287-024-04073-9

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Stem Cell Research & Therapy

ISSN: 1757-6512