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Page 2 of 9 Tsai et al. Vessel Plus 2021;5:9 I http://dx.doi.org/10.20517/2574-1209.2020.73

INTRODUCTION
Owing to the aging global population, the socioeconomic burden of stroke is increasing, and stroke has
[1]
become the second most common cause of death . In Taiwan, the prevalence of stroke in those aged > 35 years
[2]
[3]
has been reported as 5.95/1000 people . Stroke in patients can cause long-term disability , and recovery
[4]
is not expected within five months . After this period, surviving patients are regarded as having had
[5]
a chronic stroke and require long-term rehabilitation . Although mobility can be partially recovered,
neurological deficits resulting from neuronal loss are difficult to repair ; therefore, novel treatment
[4]
methods are urgently required.
Patients with acute stroke are generally treated using thrombolysis intravenously with tissue plasminogen
activator (tPA) within 3 h ; however, thrombolysis therapy can cause complications such as intracranial
[6]
[7]
hemorrhage, angioedema, and major systemic hemorrhage in 6%, 5%, and 2% of patients, respectively .
Concomitant rehabilitation is important for stroke recovery as it can reduce disability, promote recovery,
[5]
and improve quality of life . Despite investigations into transcranial magnetic stimulation, there is no
definitive evidence of the efficacy of this approach, while the administration of ion-channel mediators (e.g.,
[8]
dalfampridine) and catecholamine agonists (e.g., amphetamine) has proven to be ineffective .

Owing to the current shortage of effective therapies, it is important to develop novel therapeutic modalities.
For instance, granulocyte colony-stimulating factor (GCSF) has been reported to modestly improve
[9]
outcomes by enhancing the generation of endogenous stem cells . A growing body of evidence has
[10]
shown that stem cell therapy could help to reconstruct neuronal circuits after chronic stroke ; therefore,
exogenous stem cell transplantation could underlie the next generation of therapies for patients suffering
from stroke. In this review, we discuss current evidence and the progress of stem cell therapy in stroke
patients that has been made in our hospital (Hualien Tzu Chi Hospital, Hualien, Taiwan).

STEM CELL THERAPY IN STROKE
Stem cell therapies for stroke aim to repair, replace, and enhance the biological function of damaged or
dead cells to restore neural integrity . For instance, differentiated neuronal progenitor cells may repair
[10]
the functional neurons circuitry, and the paracrine factors that they secrete can promote the survival,
differentiation, and migration of endogenous penumbral progenitor cells . Until now, the majority of
[11]
clinical trials for stroke have used cultured autologous mesenchymal stem cells (MSCs) derived from bone
[10]
marrow, adipose tissue, or umbilical cord administered via intravenous transplantation, which is a simple
[10]
delivery technique that has been approved by government regulations .
PRECLINICAL MODELS
The variants of MSCs include umbilical cord blood (UCB) mononuclear cells (MNCs), human umbilical
cord mesenchymal stem cells (HUCMSCs), bone marrow stem cells (BMSCs), and adipose tissue-derived
stem cells (ADSCs), whereas endogenous stem cells include peripheral blood CD34 cells, GCSF-induced
CD34 cells, and neural stem cells (NSCs) . Each different type of stem cell has a different effect on stroke
[12]
recovery; however, MSCs are currently the most widely used cell type for stroke therapy [10,11] . In this
section, we introduce different types of stem cells used in preclinical research.

Umbilical cord blood mononuclear cells
Human UCB contains numerous hematopoietic and endothelial primitive cells that display strong
replication capacities in vitro and in vivo. In addition, the high levels of EGF, VEGF, G-CSF, and IL-10 in
UCB suggest that treatment with UCB could both restore immune homeostasis and enhance the repair
of damaged neurons in patients with cerebral stroke . Human UCB MNCs have been shown to exert
[13]
robust therapeutic effects in experimental models of acute and subacute stroke. For example, intravenous