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Bioinformatics of the Brain

(NCT03119636) was lastly documented as standing at phase I/IIa [116]. Var-

ious pre-clinical studies are ongoing unabated to translate different kinds of

PSCs to clinics, and clinical trials have been proceeding with encouraging

outcomes for PD treatment [117].

2.3.3

Multiple Sclerosis (MS)

Multiple sclerosis (MS) is an inflammatory autoimmune disease targeting the

CNS. Progressive MS pathology is caused by the demyelination and destruc-

tion of the axons in nerve cells. Demyelination-related neuronal damage re-

sults in atrophic lesions both in the brain and spinal cord. The main reason

behind the neuronal damage is an inflammation-driven lymphocyte attack.

Activated lymphocytes (B cells and T cells) infiltrate the CNS by surpass-

ing the brain-blood barrier. Additionally, these immune cells are accumulated

within the meninges. The secretion of inflammatory cytokines from T and B

lymphocytes stimulates astrocytes and microglia. The secretion of autoanti-

bodies along with cytokines from maturated B cells augments inflammation

around the nerve cells [118]. Consequently, immune cells inside the CNS lead

to demyelination and axonal damage. Mononuclear phagocytes gather around

the demyelinating lesions to endocytose myelin remnants. Meanwhile, proin-

flammatory phagocytes also generate reactive oxygen and nitrogen species,

cytokines, and chemokines, which expedite neuronal cell death [118, 119].

Even though iPSCs and iPSC-derived organoids are exploited for MS-specific

disease modeling [120], mesenchymal stem cells (MSCs) and hematopoietic

stem cells (HSCs) are broadly used for studies aimed at MS treatment.

2.3.3.1

MSCs and HSCs in MS Treatment

As mentioned above, MSCs are capable of modulating immune cell activation,

inflammation, cell survival, and cell signaling via different kinds of molecules

(cytokines, DNA, small RNAs, and paracrine factors) secreting directly or

inside EVs. Principally, these molecules have been evidenced to have remedial

impacts on autoinflammatory lesions in the CNS related to MS disease.

There has been contrary evidence about MSC utility in animal models

reported in the literature. Although transplantation of mouse BM-MSCs into

the MS mouse model could amend T cell (CD4⁺ and CD8⁺) activation, inflam-

matory cytokine production, and phagocytic cell functions in the secondary

lymph organs, these positive outcomes were not reflected in the CNS of the

experimental autoimmune encephalomyelitis (EAE) model, as expected [121].

Otherwise, intravenous administration of murine AD-MSCs illustrated ther-

apeutic effects in the EAE model, the well-accepted platform for MS-specific

preclinical studies. Injected AD-MSCs were detected as distributed in the

EAE lesions in the spleen, brain, and spinal cord. Interestingly, these cells en-

abled neurogenesis within the lesions, besides controlling neuroinflammation

and self-reactive T-cell responses and allowing remyelination and regeneration