Therapeutic Potential of Stem Cells in Neurodegenerative Diseases

57

[122]. Comparable regenerative and immunomodulatory effects of BM-MSCs

were acquired in MS models as well [123, 124]. Administration of xenogenic

human MSCs from different sources (umbilical cord, bone marrow, and placen-

tal tissues, etc.) in rodent EAE models also yielded promoting achievements,

particularly modulation of self-reactive T lymphocytes and elimination of au-

toreactive B cell antibodies [118, 125]. MSC-derived EVs, or secretome, were

also shown to mitigate demyelination, autoimmune reactions, and atrophic

lesions within the brain and spinal cord of animal models, apart from the cells

themselves [126–128]. Eventually, such preclinical investigations gave rise to

numerous clinical trials for MS treatment in distinct locations worldwide (Clin-

icalTrials.gov). The majority of these clinical trials in phases I and II, which

generally employed autologous bone marrow- and adipose tissue-originated

MSCs, have been in progress with plausible outcomes and safety.

Hematopoietic stem cells (HSCs) or the whole bone marrow, where HSCs

are primarily homed, are another alternative that has come out of preclinical

animal studies with excellent implications. As known, autologous HSC trans-

plantation (AHSCT) and bone marrow transplantation (BMT) have safely

and efficiently been employed to cure hematopoietic disorders and autoim-

mune diseases in clinics for over 30 years [129]. In this regard, AHSCT and

ABMT principally enforce resetting the hematopoietic system, including ir-

regular immune cells, in multiple sclerosis. AHSCT pursues six basic steps:

1) stimulation for HSC mobilization in the bloodstream through disruption

of niche interactions by chemotherapeutic agents or growth factors like cy-

clophosphamide, granulocyte colony-stimulating factor (G-CSF), etc.; 2) ab-

lation or collection of mobilized HSCs from the body by apheresis; 3) re-

conditioning isolated HSCs in a GMP-certified laboratory; 4) wipe-out or

suppression of the immune system by chemotherapy; 5) reinfusion of recon-

figured HSCs into the recipient’s blood circulation; and 6) patient follow-up

for intended and side effects. Notably, HSC conditioning is momentous for

the success of transplantation since it enables the eradication of autoreactive

lymphocyte clones, restoration of self-tolerance, normalization of gene and

miRNA expression, and orchestration of inflammatory actions [130].

As explained previously, AHSCT and ABMT in rodent models were able

to reorchestrate T cell and B cell activity and provide concomitant therapeu-

tic effects in EAE mice [118, 131]. Accordingly, AHSCT has steadily been

administered to approximately 5000 human beings with MS based on the

same rationale (clinicaltrials.gov). Most MS cases could benefit from AHSCT,

with modest improvements in pathological symptoms and overall survival af-

ter transplantation [118, 132]. Nevertheless, there are still debates and issues

about relapse risk, efficacy, and adverse events [132, 133]. Efforts to develop

more eductive and accurate methods for HSC conditioning, patient selection,

and transplantation should continue, albeit with considerable advances in

HSC-based cell replacement therapy for multiple sclerosis.