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Page 4 of 9 Tsai et al. Vessel Plus 2021;5:9 I http://dx.doi.org/10.20517/2574-1209.2020.73

Although the intracerebral implantation of PBSCs has shown efficacy in experimental models of stroke,
this strategy is highly invasive [28,29] , and other studies have also improved neurological function in
animal models using MSCs delivered via intravenous or intra-arterial routes [30,31] . In particular, bone
marrow mesenchymal stem cells reduced apoptosis and neuro-inflammation around the infarct region
and enhanced angiogenesis by accumulating extensively around the infarct area and differentiating into
[32]
neuronal or glial cells, as confirmed using immunohistochemical studies . Therefore, MSCs could be a
source of autologous stem cells to treat acute and chronic cerebral infarction.

As one of the extensively used stem cells with proven safety, there is increasing need to explore the
therapeutic potential of genetically-engineered MSCs with the aim to expand its application and increase
its efficiency of integration into stroke lesions. The advantages of MSCs include the ability to locate
themselves to the lesioned area, rapid proliferation, anti-inflammatory effects, immunomodulatory
capability, strong release of paracrine or growth factors, and the potential to differentiate and integrate into
various cell types and tissues. Through genetic engineering methods, MSCs could be modified by insertion
of genes and their expression through viral gene transduction or a non-viral way [33,34] . This could further
maximize the treatment efficacy with adequate numbers of MSCs. For example, human MSCs transfected
[35]
with the BDNF gene through adenovirus enhanced functional recovery of stroke in rodents . Genetically-
engineered MSCs were found to have about 23-fold increased expression of BDNF, which was regarded as
one of the key growth factors not only to enable neuroprotection after stroke but also to promote neuronal
differentiation and repair of damaged brain.

Neural stem cells
Increasing evidence has also demonstrated the effect of NSCs in animal models of stroke. For instance,
the implantation of intraparenchymal NSCs around the infarct region was found to improve sensorimotor
dysfunction and motor disability [32,36] , while further analysis of the infarct area suggested that lesion
topology plays an important role in functional recovery after NSC transplantation, particularly improving
outcomes for strokes confined to the striatal area. This also highlights the importance of using a novel cell-
delivery method with instruments to maximize the treatment effectiveness of NSC implantation. Zhang et al. [37,38]
recently showed that the intracerebral microinjection instrument could deliver unprecedented numbers
of NSCs to enable better three-dimensional distribution around stroke lesions. NSC transplantation in
[39]
cerebral ischemia may contribute hypoxia-inducible factor-1alpha , while the cell-dose dependent effect
of NSCs on functional recovery suggests that a high number of stem cells is crucial to ensure adequate
[40]
neurogenesis and angiogenesis . Above all, NSCs could be used for treating cerebral infarction.

STEM CELL THERAPY IN CLINICAL TRIALS AT HUALIEN TZU CHI HOSPITAL
We previously performed several clinical trials of stem cell therapy for stroke patients. In this section, we
+
introduce GCSF, CD34 , and ADSC used as the treatment of stroke in the clinical trials in our hospital.

GCSF
Based on its capacity to mobilize stem cells and its anti-inflammatory and neuroprotective properties,
GCSF can be potentially used in a clinical setting to treat several conditions, including the treatment of
MI and stroke. Experimental models of chronic stroke have revealed the synergistic benefit of using GCSF
to stimulate the mobilization of hematopoietic stem cells via mechanisms involving increased cerebral
blood flow, survival signal transduction, and the mobilization and differentiation of endogenous stem cells;
however, the efficacy of GCSF in stroke was unclear until relatively recently.

A randomized controlled trial first demonstrated the efficacy of using GCSF to treat patients with
[9]
acute ischemic stroke , reporting significant improvements in neurological function according to the
National Institutes of Health Stroke Scale, European Stroke Scale, and Barthel Index. Several studies