Therapeutic Potential of Stem Cells in Neurodegenerative Diseases

53

(iPSC-NPCs) into the hippocampus of a transgenic mouse model for AD cor-

rected abnormalities in memory and synaptic functions [90]. Likewise, hu-

man ESC-originated cholinergic neurons were able to amend cognitive symp-

toms and memory deficits in mouse models with Alzheimer’s disease [62, 66].

Interestingly, genetically manipulated mouse ESCs and iPSCs could atten-

uate AD pathophysiology. Injection of APP gene-deleted ESC- and iPSC-

derived thymic epithelial progenitors (APP ^−/−ESC/iPSC-TEPs) induced

an increase in anti-Aβ antibodies in the mouse serum and Aβ phagocytosing

macrophages in the CNS. Thus, ESC/iPSC-TEPs resulted in the clearance of

Aβ deposits in the mouse brain and counteracted AD pathology [91].

2.3.1.4

Utilization of MSCs in AD Treatment

Mesenchymal stem cells (MSCs) obtained from different tissue sources are

frequently utilized in studies in vivo and in vitro for Alzheimer’s disease.

MSCs are closely interacting cells with their surroundings. Particularly, cell-

cell contacts and paracrine factors are essential for regulating adjacent cells’

functions. Herein, neurotrophic and angiogenic factors are notable for improv-

ing neural and glial cells. Babaei and colleagues elicited that autologous bone

marrow mesenchymal stem cell (BM-MSC) transplantation promoted memory

in age-induced Alzheimer’s models of rats [92]. MSCs do not only affect the

biological functions of neurons but also orchestrate immune cells in the brain,

such as microglia. When BM-MSCs were grafted in mice, inflammatory mi-

croglia (M1) were inhibited and anti-inflammatory microglial cells (M2) were

activated, avoiding oxidative stress and further brain damage. BM-MSCs also

drive microglia cells around Aβ-accumulated sites for clearance. Thus, BM-

MSCs are detected to improve spatial memory [93]. Treatment with extracel-

lular vesicles (EVs or exosomes) of adipose tissue-derived MSCs (AD-MSCs)

showed a decrease in apoptosis in the brain of the transgenic mouse model

of AD. AD-MSC-derived EVs were adequate to alleviate Aβ pathology [94].

Santamaria and coworkers reported similar findings: intranasal injection of

the MSC secretome into Alzheimer’s mice restored brain, memory, and recog-

nition functions by reducing amyloidosis and neuroinflammation [95]. Identi-

cally, different types of MSCs originated from the umbilical cord, Wharton’s

jelly, dental tissues, and the placenta, and/or their extracellular vesicles, have

shown outstanding results in preclinical animal models [96–100].

Besides, there are tens of ongoing or completed clinical trials for AD pa-

tients (https://clinicaltrials.gov). For example, allogenic BM-MSC transplan-

tation in 33 participants was reported as safe, feasible, and efficient to augment

neurorecognition in patients compared to placebo. Autologous AD-MSC treat-

ment still continues with 80 patients. Nevertheless, allogenic umbilical cord

MSC (UC-MSC) transplantation is a phase I study. Although it has been

reported as safe and well-tolerated, any impact on AD symptoms has not

been detected so far. Most of the clinical trials with MSCs or MSC-derived