MESENCHYMAL STEM CELLS (MSCS) AS POTENTIAL SOURCES OF TREATMENT OF NEURODEGENERATION DISEASE: A STRATEGIC REVIEW

MESENCHYMAL STEM CELLS (MSCS) AS POTENTIAL SOURCES OF TREATMENT OF NEURODEGENERATION DISEASE: A STRATEGIC REVIEW

Shreya Shreshtha, Rahul Verma, Shubham, T. S. Gopenath and Kanthesh M. Basalingappa *

Division of Molecular Biology, Department of Biotechnology and Bioinformatics, Faculty of Life Sciences, JSS Academy of Higher Education and Research, Mysuru, Karnataka, India.

ABSTRACT: Mesenchymal Stem Cells are multipotent adult stem cells that are found in tissues of the body, including umbilical lines, bone marrow, fat cells, etc. Mesenchymal stem cells incline to self–restore tissues, such as bone, fat cells, connective tissues, and microglia cells, which are obtained from the mesoderm layer and act as macrophages in the central nervous system. So, MSCs can be used to promote functional recovery in many neurological disorders. Neuroinflammation is a pathological feature of neurodegenerative diseases, which is also indicated to mediate neuronal damage and deteriorate the backward accumulation of Aβ in Alzheimer's disease. The mechanism for MSC-based therapy in Alzheimer's disease that MSCs regulate neuroinflammation by microglia activation; this will reduce pathological features such as tau hyperphosphorylation and Aβ deposits and save the spatial learning and memory deficits and their multipotentiality and secretome, based on these findings include cell therapy methods for Parkinson disease mainly focused on the ability of stem cells to differentiate into Dopaminergic neurons producing cells that will replace diseased Dopaminergic neurons. MSC-based therapeutics have been suggested for osteoarthritis. MSCs were mostly found in a thin layer of connective tissue called periosteum, lungs, milk teeth, tendon, synovial stratum, cancellous bone, adipose tissue, tendon, lung, and other tissues. MSCs associated with immune cells and have immunomodulatory effects. Moreover, the RAP1/NFkb signalling pathway controls MSC paracrine activity, which seems to be linked with Female infertility. This review will assist you in understanding many aspects of MSC and its molecular role and therapeutic applications.

Keywords: Mesenchymal stem cells (MSCs), multipotent, Umbilical cord, Bone marrow, Macrophages, Neurological disorders, Inflammation

INTRODUCTION: MSCs can be utilized to advance useful recuperation in numerous neurological issues. MSCs can likewise lessen provocative reactions by different dissolvable elements. Amidst these variables, TNF alpha –working as a crucial factor impacting properties of immunomodulatory of MSCs.

Accordingly, the specific component that causes hostile to – provocative impacts is unknown. In this investigation, we uncover that advanced M2 polarization through microglia via TSG-6 subsequently gives an enemy of the neuroinflammatory effects.

And in comparison to pluripotent stem cells, which have the risk of immune rejection and teratoma formation, adult stem cells, particularly mesenchymal stem cells (MSCs), are promoted as a suitable alternative because they also exhibit pluripotent properties. MSCs are also distinct from hematopoietic stem cells and can differentiate into multiple cell types such as adipocytes, chondrocytes, and osteoblasts. Mesenchymal stem cells are spindle-shaped cells, first derived in the bone marrow of the mid-1970s ¹. These cells are found in various adult tissues and secretions, including adipose tissues, amniotic fluid, dental pulp, menstrual blood, placenta, endometrium, umbilical cord, and foetal tissues like liver and bone marrow, blood ². MSCs are also known for their multiple effective properties like self-regeneration, self-replication, and self-repairment ^{2, 3}. These cells help in the regulation of cells and a standard cell source of tissue renewal ^{1, 4}. MSCs also explicit definite cell biomarkers like CD73, CD90 and CD105, which can be diversified into, chondrogenic and osteogenic lineages in-vitro but deficient in CD14, CD19, CD34, and CD45 ⁵. MSCs have immunomodulatory characteristics, which is one of their key benefits. In-vitro produced MSCs have the ability to interact with and influence the activity of the majority of effector cells engaged in the primary and acquired immune response mechanisms. They suppress complement-mediated proliferation of peripheral blood mononuclear cells, prevent apoptosis of native and activated neutrophils, and reduce the number of neutrophils attaching to vascular endothelial cells, restricting the mobilization of these cells to the location of injury ⁶.

MSCs regulate the whole tissue renewal mechanism by activating or suppressing the immune system once damaged tissues or cells. Toll-like receptors are one of the properties of MSCs, which help detect the threat. All the MSCs express TLR2, TLR3, TLR4, TLR7, and TLR9. The expression levels of these TLRs differ greatly depending on the tissue from which they originate Fig. 1.

FIG. 1: OUTLETS OF MESENCHYMAL STEM CELLS AND THEIR ROLE IN DISTINCT LINEAGES

TLRs are the first line of defence for the immune system, recognizing chemicals from wounded cells or infections. TLR activation can activate MSCs, which can protect cells from injury/damage. Through the recruitment of neutrophils, MSCs have pro-inflammatory effects in the early stages of inflammation. MIP1 (macrophage inflammatory protein 1), CCL5 (CXC motif ligand 5), CXCL9 (CXC motif ligand 9), and CXCL10 (CXC motif ligand 10) are secreted by pro-inflammatory MSCs, which trigger T cells by attracting additional lymphocytes. There are only minimal amounts of inflammatory markers like TNF and IFN at this stage ⁷.

In tissue engineering, mesenchymal stem cells are effective based on the earlier research. These MSCs have potential in many diseases, including neuroinflammation, female infertility, and joint disorders. Hence, in this review, we will aim for the efficacy of mesenchymal stem⁸.

MSCs in relation to Neuroinflammation: Neuroinflammation is one of the crucial pathological diseases involved in Traumatic Brain Injury (TBI) ⁹, stroke ¹⁰, intracerebral haemorrhage (ICH), and various neurodegenerative diseases ^{11, 12}. Under optimal circumstances, neuroinflammation is responsible for causing homeostasis and promoting tissue repair. Microglia plays an important role in the beginning and causes neuroinflammatory responses ¹³. Similarly, macrophages and microglial cells indicate the plasticity that could polarize towards the classical pathway of M1 or alternative M2 phenotype. M1 microglia (polarized) is characterized by increased pro inflammation cytokines that induce TNF – alpha, IL – 1 beta, and IL – 6 and increase iNOS and CD16 levels. On the other hand, M2 polarized microglia have the potential to exaggerate M2 phenotype markers like Ym – ½, CD – 206, TGF – beta, and Arg – 1. Functionally, M1 microglia disturb neural injury and retard the cellular reactor after CNS disruption, while M2 microglia can protect neurons and leads to recovery and remodelling ¹⁴.

Inhibiting M1 microglia polarization and promoting the M2 microglia polarization may be a viable strategy for treating neuroinflammation-related diseases ^{15, 16}. Several recent studies reveal that administration of MSCs is useful for promoting recovery of function in certain neurological disorders ^{17, 18}. Previous studies describe that MSCs also reduce the production of inflammatory factors in the microglia by TSG – 6 ^{19, 20}.

The rejuvenation and differential properties of stem cells have been shown as a very good tool for regeneration, restoration, or replacement therapies in several diseases. MSCs have great potential to differentiate into a wide variety of cells. MSCs are adherent cells with a fibroblast-like appearance that can distinguish into bone cells, cartilaginous cells, fat cells, tonocytes, and myocytes ^21-26. MSCs are also responsible for hematopoiesis, including Erythropoiesis, Leucopoesis, thrombopoiesis, and also possess immunomodulatory properties. Many growth substances, chemokines, adhesion molecules, and TLRs ^{27, 28} mediate the migration of MSCs. They are also successfully used to reverse - graft – versus – host disease in those patients who receive Bone-Marrow transplants ^{29, 30} and in those identified with the Resistance to Steroids ^31-33. MSCs have the potential to reduce the swelling initiated by regulative T-Cells and decrease the destruction of kidneys and bowel ^34-39.

Immunomodulatory Role of MSCs: MSCs are useful as the best tool for cell therapy, particularly for the control of disorders caused due to inflammation based on their immunostimulatory properties, paracrine cell signaling via stimulating characteristics, namely anti-apoptotic, anti-fibrotic and anti-angiogenic ^{40, 42}. MSCs are also useful in a wide area of the immune system triggered by inflammatory factors produced by activated immune cells, i.e., IFN – gamma, IL – 1 Beta, and TNF – alpha ^43-50.

Several studies reveal that MSCs may display immunosuppressive or immunomodulatory properties ^{43, 51, 52-55}. MSCs also tend to reduce the effects of b inflammatory and protect against the Cytokine Storm. MSCs are placed on the ruptured sites because of hypercytokinemia ⁵⁶, which switches on the immune system. The movement and activation of mesenchymal stem cells may also bring out several growth and immunomodulatory factors by secreting them. Based on the small protein involved in cell signaling known as cytokines (whether the signal is acute or prolonged inflammation), MSCs begin the immunomodulatory response and heal the ruptured sites and impotent to suppress the continuing prolonged inflammatory signals outcome of cellular fibrosis ^{57, 58}.

How Mesenchymal Stem Cells play its Role in Alzheimer disease: By 2006, the world occurrence of Alzheimer's illness was 26.6 million. By 2050, the occurrence will quadruple, whereby 1 in 85 individuals around the world will be dealing with the illness ^59-61. Frequently suggested medications for dementia remain inhibition of cholinesterase and memantine (Namenda) for long-term use and are considered toxic. Thus, MSCs are the best alternative. They are thought to have superiorities in substantial resources (for example- umbilical cord in humans, adipose tissues and bone marrow), with a decrease in immunogenicity and atypicality self-renewal behavior ⁶².

Studies had shown that when Aβ-managed neuronal progenitor tissues (NPCs) co-cultured along with MSCs, they boosted the expression of proliferation marker (Ki-67) considerably, neuronal progenitor markers such as (GFAP, nestin, SOX2), as well as a neuronal marker (HuD) compared with Aβ therapy alone. On top of that, MSC therapy during Aβ-treated NPCs (neural progenitor cells) boosted the articulation of Ngn1 and also β-catenin compared with Aβ treated alone and quantitative analysis revealed that the variety of BrdU, as well as HuD dual positive cells in dentate gyrus, was actually considerably greater in the MSC-treated group compared to after Aβ treatment alone. These show MSCs significantly enhance neurogenesis in hippocampus area and enhance the NPCs differentiation (neuronal progenitor cell) into more mature neurons in AD models by activation of signaling pathway i.e., Wnt pathway ⁶³.

The hMSC (Human mesenchymal stem cell) therapy considerably reduced LPS‐induced microglial activation, tumor necrosis factor (TNF)‐α, inducible nitric oxide synthase (iNOS) mRNA phrase, and also the creation of NO compared to the LPS‐only therapy. MSCs might directly or indirectly control the condition of astrocytes or microglia and rely on TFs signifying paths to readjust the equilibrium of inflammatory cytokines, consisting of each pro-inflammatory and anti-inflammatory cytokines ^{62, 64}. Nevertheless, the underlying systems of MSC treatment for AD stay uncertain. Neuronal reduction in AD is actually partially compensated through MSC transplantation as well as this might be among the mechanisms for MSC treatment in AD ⁶⁵.

Mesenchymal Stem Cell Role in Parkinson Disease: Parkinson is a gradual neurodegenerative disease because ofmassive damage of dopaminergic neurons in area nigrostriatal pathway and neuron loss in substantia nigra pars compacta which results in debilitating movement disorders ⁶⁶. New treatment for PD using different animal models uncovered unusual neurotoxins ⁶⁷. One among these models’is 1-methyl-4phenyl-1,2,3,6-tetrahydropyridine (MPTP) animal model exposed to these neurotoxins that helped to determine the pathophysiological mechanism of PD and currently injured rat exposed to 6-OHDA neurotoxin are most used in PD model ^{68, 69}. There are 2 properties that discuss the regenerative prospective of MSC's: their multipotentiality and secretome. Based on these findings cell therapy strategies for Parkinson disease mainly focused on the ability of stem cells to differentiate into Dopaminergic neurons producing cells that will replace diseased DA neurons ⁷⁰.

Mesenchymal Stem Cells in Osteoarthritis: Osteoarthritis is one of the prevalent disorder of joints, which causes discomfort and stiffness of joint movements in an individual. In this, articular cartilage decays and the formation of new bone occurs at the same position. OA is commonly observed and leading cause of physical disability in aged individuals, which makes them incapable of doing physical activities. OA occurs in all the synovial joints of an individual which mainly affects the hips and knee movements as well as it also brings out other disorders like depression and sleeping disorder ⁷¹. OA is differentiated into two categories: 1) Genetic factor and 2) Aging.

Particularly, MSC-based therapeutics has been suggested for osteoarthritis. MSCs were mostly found in a thin layer of connective tissue called periosteum, lungs, milk teeth, tendon, synovial stratum, cancellous bone, adipose tissue, tendon, lung, and manymore tissues(9). OA might be the outcome of MSC population malfunctions, leading to a degeneration of bones ⁷².

Mesenchymal Stem Cells in Female Infertility: In earlier studies, it has been observed that MSCs play an important role in several diseases, including infertility. Infertility in women impacts the quality of health and well-being of women and their families. Infertility can be caused by female reproductive disorders, which are represented in Fig. 2. Several conditions like POF, PCOS, Asherman syndrome, endometriosis and fallopian tube obstruction, primary ovarian insufficiency, polycystic ovary syndrome, endometriosis, and fallopian tube obstruction ⁷³. Primary ovarian insufficiency, generally called POF, occurs in women below 40 years, affecting 1% of the total women population in the world ⁷⁴. Polycystic ovary syndrome, PCOS, is described by increased level of androgen, irregular menstrual cycle, and tiny pouch-like structure on a single or on the pair of ovaries⁷⁵. During the menstrual cycle, the dense innermost layer formation on the uterus known as endometriosis can cause infertility. Asherman syndrome is an acquired disorder ^76, and fallopian tube obstruction occurs due to the blockage in women's fallopian tube. All these symptoms are the main causes of infertility in women worldwide ⁷⁷.

MSCs treatment for Neuroinflammation: Macrophages and microglia are immune cells that tend to change their phenotypic expression into anti-inflammatory cytokines and prevent damaged neural tissue. In this type of condition, mainly therapies can be used, which will regulate the immune system after Brain ischemia; that is, transplantation of MSCs is getting more success. In earlier research, it has been observed that MSCs are capable of regulating immune response and help information of astrocytes, maturation of nerve tissues, formation of oligodendrocytes, and angiogenesis. Also, damaged cells can be replaced by the paracrine effect, but its release in the environment extracellular vesicles (EV), plays a crucial role. EVs are membrane structures having essential biomolecules such as proteins, lipids, and nucleic acids. Also, they have the potential to explicit the autologous properties as the cells have (from where they are obtained). Therefore, EVs have a decreased immune responseability and cannot blockage the vessel, and have the potential to cross the Blood-Brain Barrier, or we can say BBB. Some studies reveal that MSCs and EVs have immunosuppressive and prevent neural cell death; however, they can stimulate the development of nerve tissues, angiogenesis, and so on. For illustration, the figure is given in Fig. 2.

FIG. 2: EFFECTS OF MSCs ON DIFFERENT IMMUNE CELLS

Alzheimer disease and Inflammation: Alzheimer's disease occurs due to Aβ plaques and intracellular NFTs. Microglia and Astrocytes play a critical role in neuroinflammation ⁷⁴. It is observed that microglia and β-amyloid plaques in pathogenesis or progression from the neuroimaging analyses in AD of transgenic rodent models, post-mortem human brain. Microglia is recognized for its anti-inflammatory effects and pro-inflammatory ⁷⁵. Additionally, Aβ can trigger microglia to produce cytokines and neurotoxins, thus promoting neurodegeneration ⁷⁶. Astrocytes are the most abundant kind of glial cells in the main nerves (CNS) and have a lot of operations, consisting of preservation of ionic stabilization, blood-brain obstacle (BBB), and involvement in synaptogenesis, neurogenesis and also synaptic transmission. Astrogliosis happens in AD, and also the level of astrogliosis changes is connected with cognitive problems. Astrocytes reveal a number of receptors for chemokines and also inflammatory cytokines consisting of those like IL-1β and also TNF-α ⁷⁷.

FIG. 3: IMPACT OF MSC-IMMUNOMODULATED MICROGLIA ON AD PROGRESSION. MSCs INFLUENCE THE ACTIVITY STATE OF MICROGLIA, M1(CLASSICALLY ACTIVATED) OR M2 (ALTERNATIVELY ACTIVATED), IN PARACRINE OR AUTOCRINE MANNERS, AND THEN IMMUNOMODULATE THE HOMEOSTASIS OF NEUROINFLAMMATION FOR A RESTORE TO THE NORMAL HEALTHY CONDITION

FIG. 4: EFFECT OF MSC-IMMUNOMODULATED ASTROCYTES ON AD PROGRESSION. MSCs AFFECT THE ACTIVITY STATE OF ASTROCYTES BY AUTOCRINE OR PARACRINE MANNERS, AND THE ACTIVATED ASTROCYTES IMMUNOMODULATE THE HOMEOSTASIS OF NEUROINFLAMMATION AND FACILITATE A RETURN TO THE NORMAL HEALTHY CONDITION

MSC Therapy for AD: Microglia-mediated Neuroinflammation: MSCs have greater potential for AD therapy because of no immune rejection. Mechanisms of MSC therapy for AD require further exploration. MSCs have been transplanted into various AD models, and patients with AD show us the immune-modulatory role in AD development by microglia ⁷⁸. Systemic replacement of human umbilical cord blood-derived mesenchymal stem cells (hUCB-MSCs) into APP/PS1 transgenic mice shows a reduction in the level of interferon-γ (a pro-inflammatory cytokine), increased the levels of IL-10 and transforming growth factor-β1 (anti-inflammatory cytokines) in peripheral plasma and reduce Aβ plaque deposition as well as soluble Aβ which may be related to activation of microglia ⁷⁹ Fig. 4. MSC therapy promote an increase in IL-4, which induce microglia to produce insulin-like growth factor (IGF)-1 ⁸⁰. Reduce Aβ toxicity and boost Aβ phagocytosis ⁸¹.

MSC transplanted in the AD model triggered microglia to become activated and covert into an amoeboid shape and reach the area of inflammation. Activated microglia has two phenotypes: M1 (classical activated) and M2 (alternatively activated) ⁸². M1 microglia usually produces massive pro-inflammatory cytokines inducing IL-1β, IL-12, TNF-α, and iNOS, which worsens the CNS damage ^{83, 84}. M2 microglia respond to IL-4, IL-10, IL-13 and TGF-β, which have an anti-inflammatory impact on AD ⁸⁵. Interestingly, transplanted MSC decreased Aβ deposition and improved neurological function ^{86, 71}. By anti-inflammatory cytokines are considered to favour AD improvement ⁸⁷. It is seen that activated cytokines can switch between M1 and M2 phenotype by a dynamic process with importance ⁸⁸. A mechanism can be of MSC-based therapy in AD that MSCs regulate neuroinflammation by microglia activation. This will reduce pathological features such as tau hyperphosphorylation and Aβ deposits, and save the spatial learning and memory deficits Fig. 5.

MSC Therapy for AD: Astrocyte-mediated Neuroinflammation: Studies in APP/PS1 transgenic mice revealed that hypoxic MSC-derived exosomes might efficiently decrease the inside build-up of synaptic protein expression in the brain cells of these mice. Additionally, therapy with exosomes coming from hypoxic MSC reduced activation of glial tissues and degrees of inflammation throughSTAT3 and NF-kB pathways. Exosomes coming from hypoxia-preconditioned MSCs efficiently enhanced the level of miR-21 in the brains of AD mice, which avoided the pathologic conditions in AD mice ⁸⁹. Astrocytes make up a particular tissue kind along with a star-shaped morphology resembling inactivated microglia surrounded by close-by neurons and capillary ⁹⁰ and have lots of essential features consisting of metabolic impacts as well as modulatory impacts on the neuronal microenvironment under physiological conditions ⁹¹. Nonetheless, many triggered astrocytes hasbeen found adjacent to Aβ plaques, suggesting an interaction between activated astrocytes and AD development ⁹². MSCs might participate in a restorative function in AD by reducing astrocytes' activation. Furthermore, when MSCs are put on the microenvironment of injured cells, they can easily create different elements like TGF-β as well as IGF-1 that trigger the activation of astrocytes. Consequently, the triggered astrocytes can easily clear Aβ plaque deposition as well as which likewise might trick TGF-β ⁹³ as well as IGF-1 ⁹⁴ as neuroprotective elements. Nevertheless, the activation of astrocytes has both advantages and disadvantages. Extreme activation of astrocytes can easily result in astrogliosis colocalized along with amyloid plaques in AD ⁹⁵ or even glial mark development after CNS damages ^96-97.

Wnt Signalling in Alzheimer’s disease: Microglia governs the inherent defense inflammation to prevent the brain and helps in improving the performance of CNS ^{98, 99}. Neuroinflammation has been established as the central pathophysiological pathway of multiple neurodegenerative disorders and microglia are important for neuroinflammation throughout the brain ^100-102. Microglia has a double impact on the prevalence of Alzheimer's disorder ¹⁰³.

Microglia destroy amyloid-beta (Aβ) to prevent it from forming. They discharge inflammatory and pro-inflammatory factors that contribute to neuroinflammation and the proliferation of tau NFTs and amyloid plaques and pathology ¹⁰⁴. The signal transduction pathway called Wnt signaling pathway acts as a vital factor in determining cell lineage and activity. Both pathological tau phosphorylation and synaptic failure in AD are caused by Wnt pathway dysregulation ¹⁰⁵. The regulatory role of Wnt signalling on microglial inflammation has also been verified in recent studies ^106-110.

Wnt signalling is involved in the improvement, renewable and pro tumor etiology of entirely important organs of the body. Wnt signals in the brain helps in vascular healing and the formation of the blood-brain barrier and communicate with microglial neuroinflammation ¹¹¹. Both the canonical and non-canonical pathways as well as their cascade components, help compensate Wnt signals ^{112, 113} Fig. 5. High levels of CR3 namely CD68, IBA1, CD11b and CD33 expression shows the pro-inflammatory activity of altered microglia due to stimulation of Wnt canonical pathway. Yet, as per the existing research, ifWnt signalling has a significant impact on microglial devour is uncertain ^{113, 114}.

FIG. 5: ROLE OF WNT SIGNALLING IN ALZHEIMER’S DISEASE

Even though microglia are not constitutive components of the CNS, we have demonstrated that they are very closely linked to NPCs, neurons, and other glial cells. Glia consisting of small cells are considered more than immune cells in the CNS as immunological executors. It also impacts neuronal renewal through their interactions with nerve cells, myelinating cells of CNS called oligodendrocytes and astrocytic glial cells, as the importance of Wnt pathways in tissue regeneration has been generally recognized. Microglia plays an important role when cellular aging results in neurodegenerative disorders as these glial cells alter themselves into active form and oppose epidemiological changes of these disorders. Also, it triggers neurodegeneration by inflammatory and immune response ¹⁰⁵.

Therapeutic use of MSCs in Parkinson: Secretome consists of a group of paracrine factors mainly formed by cytokines that modify the immune response or the functioning example interleukin-6 (IL-6), prostaglandin E2 (PGE2), and growth factor-beta (TGF-β) ^{115, 116}. These cytokines inhibit the cytotoxic T lymphocyte proliferation cytokines and stimulate the proliferation of regulatory T lymphocyte ¹¹⁷. But also, this neurotropic or neuroprotective activity on resident progenitor cells, hence inducing neurogenesis /oligodendrogenesis or anti-apoptotic effects on neuron or glia cells, neurite outgrowth ¹¹⁸ and angiogenesis ¹¹⁹. Therefore, secretome can help in limiting the process of neuroinflammation and can reverse the damage caused by PD.

Additional therapeutical significance of the ability of MSC to move to the wounded tissue and inflammation is due to signals generated by different factors that are released at these sites ¹¹⁵. So far, little is known about MSC action in therapeutic mechanisms in these parkinsonian models. But many studies on the therapeutic potential of these paracrine factors work on the hypothesis that nigrostriatal degeneration is done by inflammation. The MSC therapeutic effect could provide some anti-inflammatory mechanism by secretome. For this study, in-vitro dopaminergic producing mesencephalic neurons and mouse microglia are activated by lipopolysaccharides (LPS) were co-culture with human bmMSC; the result shows a remarkable decrease in microglia activation and death of neurons also the amount of pro-inflammatory cytokines in the medium also decrease and show more neurons producing dopamine as compared to control group ¹²⁰. This result suggests that MSC role as a potential therapeutic in treating PD is based on immuno-modulation and trans differentiative capacity and stimulates proliferation and endogenous stem-like progenitor cells differentiation found in most tissues, and decreases inflammatory and immune reactions ¹²¹. Therefore, microenvironment changes in the tissue may be more important than transdifferentiation in effecting tissue repair ^{122, 123, 124}. MSC can also help by decreasing the alpha-synuclein, which regulates synaptic vesicle trafficking and subsequent neurotransmitter release, by increasing the autophagic process to reduce the accumulation of alpha-synuclein in PD patients ^125,126. When MSC was co-cultured along with neuronal cells and MPP+ (which is an active form of MPTP toxin), alpha-synuclein decreased, and LC3-II level increased, expressing a high number of autophagosomes indicating stem cells can be supplied the survival of dopaminergic neurons.

FIG. 6: LRRK2 AS WELL AS ASYN CONTROL OF AUTOPHAGY AT THE PRESYNAPTIC TERMINAL. ADDITIONALLY, PD- CONNECTED PROTEINS ACT UPON EACH SYSTEM, MOST PROBABLY MODULATING A TYPICAL PROCEDURE. FOR INSTANCE, LRRK2, AS WELL AS ASYN, CONTROL AUTOPHAGIC FLUX AS WELL AS LYSOSOMAL TASK, ALONG WITH PD TRIGGERING MUTATIONS IMPAIRING THE PROCEDURE

Role of MSCs in Osteoarthritis Therapy: In recent years, clinical experiments using MSCs to cure human joint cartilage abnormalities have been conducted. It has been suggested that mosaicplasty might be useful to treat knee joint deep zone of cartilage lesions in an individual. This MSC-based therapy's therapeutic advantages contributed to the growth of MSC-based cartilage regeneration techniques. In addition, low, middle, and high-dose intra-articular injections of AD MSCsfor osteoarthritis therapy were studied. It is also found that injecting MSCs into an osteoarthritic knee improved pain and function without generating any side effects, and the renewal of articular cartilage minimized cartilage defects. By injecting joint injection of MSCs has proven to enhance a patient's condition with OA as it relieves the pain of joints and other deteriorating joint disorders, as previously indicated. The potential of MSC exosomes to limit cartilage degradation and subchondral bone disintegration, reduce osteophyte development, and prevent synovial inflammation were among the benefits of intra-articular injection of MSC exosomes for OA therapy ¹²⁷. Other MSC distribution technologies include joint injection called intra articular, fibrous scaffolds, fibrin sealant, TECs (tissue-engineered constructs) and Hyaluronic acid hydrogel-based drug delivery systems Fig. 6.

MSCs in the Treatment of Female Infertility: MSCs have efficacy in therapeutics due to their ability to differentiate into diverse cell fate and regulate modulation of immune system by regulating immune responses. Also, they have been dividing into stromal, endothelial, and epithelial cells which thickens endometrium and enhance gestation results ¹²⁸. When MSCs are kept in various cell culture conditions, theyshould be plastic-adherent. Then, MSCs surface biomarkers CD73, CD90 and CD105n expresses itself 129,130. In earlier research, MSCs played a role in diagnosing infertility by improving ovarian performance. MSC therapy in-vivo increases ovarian function and this effect may be intervening via signaling paracrine pathways. MSCs associate with immune cells and have immunomodulatory effects ¹³¹. Moreover, the RAP1/NFkb signaling pathway controls MSC paracrine activity.

In reproductive system illnesses associated with inflammation, the NFkb signalling pathway is extremely active ¹³². Such responses appear to be linked to mechanisms that promote renewal and angiogenesis, which may help ovarian function. As these pathways may modulate inflammatory immune responses, heal wounded tissues, and induce stem cell precursors to develop into particular tissue cells, this possible mechanism of MSC activity is of significant concern. Furthermore, miRNAs and exosome transfer provide a special way by which MSCs exert roles via mitochondrial transfer, a crucial factor in many biotic functions in life and illness, including premature ovarian failure ¹³³.

Certain inflammatory cytokines, such as IL-6 and TNF-, can cause MSC skeletal rearrangement and the formation of tunnelling nanotubes (TNT), which allow mitochondria to move from mesenchymal stem cells to neighbouring cells such as AECs (airway epithelial cells), cardiac muscle cells and RGC (retinal ganglion cells). MSC mitochondrial replacement to reproductive organs, including oocytes, has also been observed lately because of inflammation ¹³⁴.

CONCLUSION: It has been observed that mesenchymal stem cells' immunomodulatory properties help improve individuals' health conditions. MSC can switch cells from basal ganglia and nigrostriatal dopamine system and in many different areas of the brain, will be beneficial for Parkinson's Disease patients. As for secretome, neurotrophic factors and immunomodulatory cytokines lower neuroinflammation and provide an environment for dopaminergic neurons to survive. Also, it may function in cellular treatment or gene for the model of Parkinsonism to increase the longevity of transplanted cells. And astrocytes or even microglia regulated through MSCs might participate in greater than individual functions. In AD, Aβ plaques most probably trigger astrocytes or even microglia. It is feasible that the activation of microglia participates in an essential function in the activation of astrocytes. For this reason, the communication between the activation of microglia and the activation of astroglia might be associated with the pathogenesis of AD.

Likewise, the MSC located treatment for AD has actually complicated settings by modulating the activation of microglia or even astroglia. Wnt pathway can enhance the chances of treatment of AD in future aspects. Since MSCs have a long history of usage in joint healing, using them to treat OA is highly enticing. Animal research has provided far motivation and the reasoning for moving on with human trials.

The effective isolation and cultivation of MSCs from identified and dependable sources might be a future direction. The synthesis of different biomaterials optimizes mesenchymal stem cells' efficacy for reproductive system cells. MSC transport vehicles made of collagen-based drug delivery have also been used to improve stem cell engraftment, cell adhesiveness, and preservation. However, further work is needed to improve this method.

Footnote:

Funding: Funding information is not applicable. No funding was received.

Ethics Statement: This article does not contain any studies with human participants or animals performed by any of the authors.

ACKNOWLEDGMENT: The authors would like to acknowledge the Management of JSS Academy of Higher Education & Research, Mysuru, Karnataka, for supporting the basic research ideas and also for the resources provided.

CONFLICTS OF INTEREST: The authors declare no conflict of interest.

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     Shreshtha S, Verma R, Shubham, Gopenath TS and Basalingappa KM: Mesenchymal stem cells (MSCs) as potential sources of treatment of neurodegeneration disease: a strategic review. Int J Pharm Sci & Res 2022; 13(11): 4254-68. doi: 10.13040/IJPSR.0975-8232.13(11).4254-68.

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