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Tsai et al. Vessel Plus 2021;5:9 I http://dx.doi.org/10.20517/2574-1209.2020.73 Page 3 of 9

UCB MNC injection was found to restore impaired exercise capabilities and exert neuroprotective effects
in rodent models of cerebral stroke [13-15] . Moreover, UCB MNCs have immunomodulatory and anti-
inflammatory effects in addition to their regenerative effects and can, therefore, protect penumbral tissue
[16]
from further injury caused by inflammation after stroke .
[17]
MNCs can also exert immunomodulatory effects by changing the phenotype of splenocytes ; therefore,
intravenous MNC therapy may achieve neural protection by altering systemic immunomodulation in the
acute or subacute stages of stroke. UCB serum was also found to contain increased heat shock protein
27 levels and exert anti-senescent effects in implanted stem cells to increase stem cell engraftment and
[18]
differentiation . Importantly, MNCs and other adult tissue-derived stem cells can be easily isolated and
expanded in the laboratory, while the safety profile of MNCs has been consistently demonstrated in clinical
trials [13,14] . A recent Phase I study was the first to demonstrate that a single intravenous administration
of allogenic non-HLA matched human UCB cells is beneficial and safe for patients with acute ischemic
stroke . Therefore, UCB could be a source of allogeneic stem cells to treat acute cerebral infarction.
[16]

Human umbilical cord matrix MSCs
Human umbilical cord (HUC) is an emerging source of MSCs (HUCMSCs), which harbor rapid renewal
properties and can be acquired through painless collection procedures. HUCMSCs can be derived
from the cord lining, Wharton’s jelly, and perivascular tissue, and they can be easily differentiated into
three germ layers that promote tissue repair. Previously, we found that HUCMSCs can improve both
functional angiogenesis and neuroplasticity in animal models of stroke by upregulating β1-integrin [18,19] .
In addition, HUCMSCs can be differentiated into microglial cells; they can also be induced to produce
[20]
neuronal proteins and increase astrocyte protein glial fibrillary acidic protein levels . Furthermore, a
[21]
three-dimensional alginate scaffold has been used to effectively induce HUCMSCs to become neurons .
Therefore, HUCMSCs could be a source of allogeneic stem cells to treat acute cerebral infarction.
Hematopoietic factor and endogenous stem cell mobilization
GCSF is a growth factor that belongs to a cytokine family. GCSF can mobilize hematopoietic stem cells
from bone marrow into peripheral blood. GCSF was routinely used to treat neutropenia and to reconstitute
the bone marrow; however, hematopoietic stem cells in transplantation have recently been replaced by bone
marrow to regenerate non-hematopoietic tissues in conditions such as myocardial infarction (MI). GCSF
administration after MI has been shown to improve cardiac function and survival rates , while its anti-
[22]
inflammatory and anti-apoptotic effects can help prevent neuronal and glial pro-inflammatory cascades,
[23]
which have both been implicated in the pathophysiology of chronic ischemic injury of the brain .
Activated neutrophils can produce microvascular plugging and cytotoxic substances, which will cause focal
cerebral ischemic infarction. Thus, reducing inflammation in the stroke area may preserve against ischemic
injury of the brain. GCSF can decrease excitotoxicity in cell culture and reduce programmed cell death in
[24]
rats with cerebral ischemia . Furthermore, a seminal paper confirms that GCSF reduced the infarction
area and improved the recovery of rats with stroke by enhancing angiogenesis and neurogenesis [23,25] .
Therefore, GCSF could be used as a therapy for acute and chronic stroke.

MSCs and peripheral hematopoietic stem cells (CD34 )
+
Owing to the efficacy of GCSF, the potential of peripheral hematopoietic stem cells (PBSCs) for treating
acute and chronic cerebral ischemia was explored since the clinical use of embryonic stem cells is hindered
by ethical issues. In stem cell therapy for stroke, PBSCs are regarded as a source of hematopoietic stem cells
and are increasingly being employed for transplantation. GCSF can mobilize PBSCs from bone marrow and
[26]
increase their numbers . Indeed, intracerebral PBSC transplantation in rats with chronic cerebral ischemia
has been shown to greatly improve neurological function [26,27] . The repair mechanisms involve macrophage/
microglial cells derived from stem cells and the expression of β1 integrin to facilitate angiogenesis in the
injured brain area.