Table 1.

Summary of relevant preclinical and clinical studies targeting EPCs following stroke.

Cell-based therapies
Preclinical studies
References	Study	Model	Main outcomes
Moubarik et al. (94)	Intravenously injection of EPCs from human cord blood 24 h after transient MCAO	Rat	- A reduction in the number of apoptotic cells and reactive astrogliosis, an increase in capillary density, and a stimulation of neurogenesis at the ischemic area. - Significant functional improvement at 7, 10, and 14 days after MCAO compared to controls.
Rosell et al. (95)	Intravenously injection of EPCs from mouse spleen 30 h after permanent MCAO	Mouse	- Significant increases in capillary density in the peri-infarct area, and in axonal rewiring. - Significant improvement in forelimb strength.
Garrigue et al. (96)	Intravenously injection of EPO-primed EPCs from human cord blood 1 day after transient MCAO	Rat	- The injection of EPO-primed EPCs increased their homing ability and the cerebral blood flow as well as reduced the BBB disruption and cellular apoptosis at the ischemic hemisphere on day 14 post-stroke.
Li et al. (59)	Intravenously injection of SDF-1α-transfected EPCs from human cord blood 1 week after permanent MCAO	Mouse	- Increase in blood vessel density and myelin sheath integrity, enhancement in neurogenesis, angiogenesis, as well as the proliferation and migration of EPCs. - Reduction in brain atrophy and improvement in the neurobehavioral function.
Hong et al. (97)	Intravenously injection of EPCs from mice 2 h after transient MCAO and for 7 days	Rat	- Increase in angiogenesis, and reduction in ischemic volume and gliosis at 14 days post-injury. - Increase in motor coordination at 7 and 14 days post-injury.
Wang et al. (98)	Intravenously injection of adiponectin-transfected EPCs from rat bone marrow 1 h after transient MCAO	Diabetic rat	- Decrease in the infarct area, as well as in cellular apoptosis in the peri-infarct area at 14 days post-injury. - Increase in angiogenesis in the peri-infarct area at 14 days post-injury. - Significant improvement in neurological function at 7 and 14 days post-stroke.
Kadir et al. (99)	Intravenously injection of EPCs from rat after MCAO	Rat	- Improvement in barrier protection at 3 days post-MCAO.
Clinical studies
References	Study	Main outcomes
Fang et al. (100)	Intravenously injection of autologous EPCs 1 month after acute ischemic infarction + 4 years follow up	- No significant differences in neurological or functional improvements, except for the Scandinavia Stroke Scale score at 3 months post-injection.
EPCs-Derived exosomes/secretome therapies
Preclinical studies
References	Study	Model	Main outcomes
Rosell et al. (95)	Intravenously injection of cell-free conditioned media from mouse EPCs 30 h after permanent MCAO	Mouse	- Significant increase in the peri-infarct capillary density. - Significant improvement in forelimb strength.
Maki et al. (101)	Intravenously injection of cell-free conditioned media from mouse EPCs 24 h and 7 days after permanent bilateral common carotid artery stenosis	Mouse	- Increases in vascular density, myelin, and mature oligodendrocytes in white matter. - Improvement in the cognitive function at 28 days post-injury.
Wang et al. (102)	Intravenously injection of either regular exosomes or miR-126-enriched exosomes from mouse EPCs 2 h after permanent MCAO	Diabetic mouse	- The application of miR-126-enriched exosomes were more effective in decreasing infarct size and increasing cerebral blood flow and microvascular density in the peri-infarct area. - Likewise, animals treated with miR-126-enriched exosomes exhibited higher increases in angiogenesis and neurogenesis as well as neurological functional recovery.
Pharmacological treatments targeting EPCs
Preclinical studies
References	Study	Model	Main outcomes
Lee et al. (103)	G-CSF treatment given 2 or 24 h or 4 or 7 days after transient MCAO and maintained for 3 consecutive days.	Rat	- G-CSF treatment increased the cerebral vasculature and the proliferation of endothelial cells compared to the control group. - G-CSF treatment improved the behavioral recovery and reduced the infarct volume, the inflammatory infiltration, the BBB disruption, and the hemispheric atrophy compared to controls. - Specifically, G-CSF applications starting at 2 h, 1 or 4 days after ischemia resulted in a better functional recovery and a greater reduction in hemispheric atrophy than injection starting at day 7. Moreover, the G-CSF injection starting at 1 day induced larger endothelial proliferation compared with injection starting at 7 days.
Pellegrini et al. (104)	EPCs transplantation + EPO treatment given 1 or 2 or 3 days after transient MCAO and maintained for 3 consecutive days.	Rat	- The combination of EPCs + EPO treatment showed the best improvement in early and long-lasting neurological status. - EPCs + EPO also was the most effective approach to decrease apoptosis and to increase angiogenesis and neurogenesis in the ischemic area compared to controls and groups receiving EPCs or EPO alone.
Wang et al. (105)	Atorvastin or G-CSF or G-CSF+SDF-1 treatments given either pre- or post-transient MCAO	Rat	- The combination of G-CSF + SDF-1 showed the best results by improving neurological performance, reducing both cerebral infarction and blood-brain barrier disruption, and promoting greater angiogenesis in the ischemic brain.
Dong et al. (106)	8 weeks of piperlongmine treatment prior to permanent MCAO.	Mouse with hypercholesterolemia	- Enhancement in the angiogenic ability of EPCs. - Reduction in the infarct volume. - Improvement in the neurobehavioral outcome.
Clinical studies
References	Study	Main outcomes
Schäbitz et al. (107)	Intravenously administration of G-CSF treatment (30 or 90 or 135 or 180 μg) within 12 h after ischemia onset and for 3 days	- No significant differences in the clinical outcome. - A beneficial effect was found linked to dose-dependent only in patients with DWI lesions between 14 and 17 cm3.
Alasheev et al. (108)	Subcutaneously administration of G-CSF treatment (10 mg) within 48 h after ischemia onset and for 5 days	- No significant difference in cerebral infarct volume between the experimental and control groups.
Floel et al. (109)	Intravenously administration of G-CSF treatment (10 μg) at least 4 months after ischemia insult and for 10 days	- No significant effect of the treatment on the test of hand motor function.
Sobrino et al. (110)	Orally administration of citicoline treatment (2,000 mg) within 24 h after stroke onset and for 6 weeks	- The administration of citicoline increased the concentration of EPCs, with better benefits when combined with rtPA. - There was a reduction of infarct growth as well as neurological and functional improvement at 3 months post-stroke.
Ringelstein et al. (111)	Intravenously administration of G-CSF treatment (135 μg) within 9 h after ischemia onset and for 3 days	- G-CSF treatment did not show significant results in mRS and NIHH scores at day 90, neither in Barthel index and infarct size at day 30. - A trend was observed regarding reduced infarct growth in the G-CSF group.
Mizuma et al. (112)	Intravenously administration of G-CSF treatment (150 or 300 μg) within 24 h after ischemia onset and for 5 days	- Clinical outcome scores did not show any significant difference at 3 months.