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

have subsequently explored the benefits of GCSF in acute ischemic stroke; however, the extent of the
improvements caused by GCSF may vary between patients due to hemorrhagic infarct transformation,
alterations in the blood-brain barrier, overly astrogliosis, and polarized immune cell alteration after GCSF
administration [9,41,42] . In addition, dose-dependent immunomodulation has been shown to alter the central
nervous system-specific effects of GCSF after stroke; therefore, optimizing the dose or treatment time may
[43]
help overcome this drawback and provide consistent efficacy during the use of GCSF . Above all, GCSF is
successfully used in the treatment of stroke patients.

+
Bone marrow MSCs (CD34 )
Given the preclinical evidence demonstrating the additional benefits of intracerebral PBSC implantation in
animal models of chronic stroke, we initiated studies to explore the benefits of PBSCs. Among 30 chronic
stroke patients, GCSF-treated group and stereotactic PBSC implantation displayed the most improvement
[28]
in all functional characteristics . Furthermore, MRI diffusion tensor imaging revealed that the implanted
PBSCs ameliorated fiber tract disconnection caused by cerebral ischemia, and motor-evoked potential via
transcranial magnetic stimulation was shown to establish neurophysiological re-connection. Therefore,
CD34 mobilized by GCSF is successfully used in the treatment of stroke patients.
+
MSC and adipose-derived stem cells
MSCs are the most common stem cells used to treat stroke, with bone marrow- and adipose tissue-derived
[44]
stem cells being the most explored cell sources , since autologous stem cells can be used to treat acute
[45]
or chronic stroke without carcinogenicity, immune rejection, or ethical concerns . In particular, ADSCs
can be obtained from subcutaneous adipose tissue fragments or liposuction aspirates easily. ADSCs can be
expanded in vitro, and there are no ethical concerns regarding various clinical applications. The autologous
ADSCs administration into the injured penumbra for chronic stroke patients was shown to result in
functional regeneration [46,47] ; therefore, we undertook the first Phase I clinical study using the stereotactic
implantation of autologous ADSCs to treat patients with chronic stroke at Hualien Tzu Chi Hospital in
Taiwan. Our preliminary results indicate good safety and significantly improved sensorimotor function
in the study participants. Above all, ADSC could be safely and effectively used in the treatment for stroke
patients.

ADMINISTRATIVE PATHWAY AND TRANSPLANTED CELL NUMBERS
Previous clinical studies have utilized several different cell-transplantation techniques. For instance, in the
MultiStem study, patients were administered 1200 million cells via intravenous (IV) injection . Although
[48]
IV route is considered noninvasive and facilitates drug administration, some preclinical studies have
suggested that most of the stem cells in circulation will be trapped in the lungs and liver, thus stem cells
[49]
were not able to cross the blood-brain barrier . Moreover, chemotactic signaling from the injured brain
[50]
areas is not active during chronic strokes . The primary mechanism of intravenous circulated stem cells
may be contributed by reducing immune response in the stroke subacute phase. A Phase II trial of subacute
stroke has reported that intravenous administration of bone marrow-derived mononuclear cells is safe but
[51]
does not affect measures of neurological function .
Stem cells can be administered by intra-arterial route to transfer into the brain directly; however, there is
concern that this method could result in possible cell clumping, leading to microthrombi and potential
+
[52]
[53]
damage . Sung et al. conducted a Phase I clinical trial in which circulation-derived autologous CD34
cells (3.0 × 10 cells/patient) were isolated and administered via intra-carotid artery transfusion to elderly
7
+
patients with chronic ischemic stroke. To avoid microembolization, the CD34 cells were first filtered with
an embolic protection filter, slowly transfused into the ipsilateral internal carotid artery, and finally into
[53]
the infarct area . Although the neurological recovery achieved by intracerebroventricular (ICV) ADSC
administration was found to be superior to that achieved via the IV route , the invasive procedure to
[54]