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Transplantation of vascular cells derived from human embryonic stem cells contributes to vascular regeneration after stroke in mice.

Oyamada N, Itoh H, Sone M, Yamahara K, Miyashita K, Park K, Taura D, Inuzuka M, Sonoyama T, Tsujimoto H, Fukunaga Y, Tamura N, Nakao K - J Transl Med (2008)

Bottom Line: We examined the potential of vascular cells derived from human ES cells to contribute to vascular regeneration and to provide therapeutic benefit for the ischemic brain.Transplanted ECs were successfully incorporated into host capillaries and MCs were distributed in the areas surrounding endothelial tubes.Transplantation of ECs and MCs derived from undifferentiated human ES cells have a potential to contribute to therapeutic vascular regeneration and consequently reduction of infarct area after stroke.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Medicine and Clinical Science, Kyoto University Graduate School of Medicine, Kyoto, Japan. kanu@kuhp.kyoto-u.ac.jp

ABSTRACT

Background: We previously demonstrated that vascular endothelial growth factor receptor type 2 (VEGF-R2)-positive cells induced from mouse embryonic stem (ES) cells can differentiate into both endothelial cells (ECs) and mural cells (MCs) and these vascular cells construct blood vessel structures in vitro. Recently, we have also established a method for the large-scale expansion of ECs and MCs derived from human ES cells. We examined the potential of vascular cells derived from human ES cells to contribute to vascular regeneration and to provide therapeutic benefit for the ischemic brain.

Methods: Phosphate buffered saline, human peripheral blood mononuclear cells (hMNCs), ECs-, MCs-, or the mixture of ECs and MCs derived from human ES cells were intra-arterially transplanted into mice after transient middle cerebral artery occlusion (MCAo).

Results: Transplanted ECs were successfully incorporated into host capillaries and MCs were distributed in the areas surrounding endothelial tubes. The cerebral blood flow and the vascular density in the ischemic striatum on day 28 after MCAo had significantly improved in ECs-, MCs- and ECs+MCs-transplanted mice compared to that of mice injected with saline or transplanted with hMNCs. Moreover, compared to saline-injected or hMNC-transplanted mice, significant reduction of the infarct volume and of apoptosis as well as acceleration of neurological recovery were observed on day 28 after MCAo in the cell mixture-transplanted mice.

Conclusion: Transplantation of ECs and MCs derived from undifferentiated human ES cells have a potential to contribute to therapeutic vascular regeneration and consequently reduction of infarct area after stroke.

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Evaluation of vascular regeneration in the striatum on day 28 after stroke in the five groups. A, Quantification of the density of human PECAM-1+ cells (%area) in the ischemic striatum in hMNC-, hES-EC- and hES-EC+MC-injected groups. * P < 0.0001. B, Quantitative analysis of the density of mouse PECAM-1+ cells (%area) in the non-ischemic striatum and in the ischemic striatum in five groups. * P < 0.05, † P < 0.01. C, Quantification of the total density of human and mouse PECAM-1+ cells (%area) in the ischemic striatum in five groups. * P < 0.05, †P < 0.01, ‡ P < 0.001.
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Figure 5: Evaluation of vascular regeneration in the striatum on day 28 after stroke in the five groups. A, Quantification of the density of human PECAM-1+ cells (%area) in the ischemic striatum in hMNC-, hES-EC- and hES-EC+MC-injected groups. * P < 0.0001. B, Quantitative analysis of the density of mouse PECAM-1+ cells (%area) in the non-ischemic striatum and in the ischemic striatum in five groups. * P < 0.05, † P < 0.01. C, Quantification of the total density of human and mouse PECAM-1+ cells (%area) in the ischemic striatum in five groups. * P < 0.05, †P < 0.01, ‡ P < 0.001.

Mentions: In the ischemic striatum, the density (%area) of human PECAM-1 positive cells was 0.05 ± 0.01% in the hMNC-injected group (n = 11), 0.66 ± 0.11% in the hES-EC-injected group (n = 7, P < 0.0001 vs hMNCs) and 0.85 ± 0.12% in the hES-EC+MC-injected group (n = 11, P < 0.0001 vs hMNCs) (Figure 5A). As shown in Figure 5B, there was no significant difference in the densities of mouse PECAM-1 positive cells among the saline- (10.3 ± 0.4%: n = 11), hMNC- (10.9 ± 0.3%: n = 11) and hES-EC- (11.4 ± 0.4%: n = 7) injected groups, although the densities were significantly higher than that in the non-ischemic striatum (5.6 ± 0.2%: n = 5). In hES-MC- (13.2 ± 0.5%: n = 7, P < 0.01 vs control, P < 0.05 vs hES-ECs) or hES-EC+MC- (13.8 ± 0.4%: n = 11, P < 0.01 vs control and hES-ECs) injected group, a significant increase in the density of mouse PECAM-1 positive cells was observed. The total vascular density estimated by summing up human and mouse PECAM-1 positive area (12.2 ± 0.6%, P < 0.05) in the hES-EC-injected group was significantly higher compared to that in the saline-injected group. Moreover, the total vascular density in the hES-EC+MC-injected group (14.7 ± 0.6%) was markedly higher compared to those in the other four groups (P < 0.001 vs control, P < 0.01 vs hES-ECs, P < 0.05 vs hES-MCs) (Figure 5C).


Transplantation of vascular cells derived from human embryonic stem cells contributes to vascular regeneration after stroke in mice.

Oyamada N, Itoh H, Sone M, Yamahara K, Miyashita K, Park K, Taura D, Inuzuka M, Sonoyama T, Tsujimoto H, Fukunaga Y, Tamura N, Nakao K - J Transl Med (2008)

Evaluation of vascular regeneration in the striatum on day 28 after stroke in the five groups. A, Quantification of the density of human PECAM-1+ cells (%area) in the ischemic striatum in hMNC-, hES-EC- and hES-EC+MC-injected groups. * P < 0.0001. B, Quantitative analysis of the density of mouse PECAM-1+ cells (%area) in the non-ischemic striatum and in the ischemic striatum in five groups. * P < 0.05, † P < 0.01. C, Quantification of the total density of human and mouse PECAM-1+ cells (%area) in the ischemic striatum in five groups. * P < 0.05, †P < 0.01, ‡ P < 0.001.
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Figure 5: Evaluation of vascular regeneration in the striatum on day 28 after stroke in the five groups. A, Quantification of the density of human PECAM-1+ cells (%area) in the ischemic striatum in hMNC-, hES-EC- and hES-EC+MC-injected groups. * P < 0.0001. B, Quantitative analysis of the density of mouse PECAM-1+ cells (%area) in the non-ischemic striatum and in the ischemic striatum in five groups. * P < 0.05, † P < 0.01. C, Quantification of the total density of human and mouse PECAM-1+ cells (%area) in the ischemic striatum in five groups. * P < 0.05, †P < 0.01, ‡ P < 0.001.
Mentions: In the ischemic striatum, the density (%area) of human PECAM-1 positive cells was 0.05 ± 0.01% in the hMNC-injected group (n = 11), 0.66 ± 0.11% in the hES-EC-injected group (n = 7, P < 0.0001 vs hMNCs) and 0.85 ± 0.12% in the hES-EC+MC-injected group (n = 11, P < 0.0001 vs hMNCs) (Figure 5A). As shown in Figure 5B, there was no significant difference in the densities of mouse PECAM-1 positive cells among the saline- (10.3 ± 0.4%: n = 11), hMNC- (10.9 ± 0.3%: n = 11) and hES-EC- (11.4 ± 0.4%: n = 7) injected groups, although the densities were significantly higher than that in the non-ischemic striatum (5.6 ± 0.2%: n = 5). In hES-MC- (13.2 ± 0.5%: n = 7, P < 0.01 vs control, P < 0.05 vs hES-ECs) or hES-EC+MC- (13.8 ± 0.4%: n = 11, P < 0.01 vs control and hES-ECs) injected group, a significant increase in the density of mouse PECAM-1 positive cells was observed. The total vascular density estimated by summing up human and mouse PECAM-1 positive area (12.2 ± 0.6%, P < 0.05) in the hES-EC-injected group was significantly higher compared to that in the saline-injected group. Moreover, the total vascular density in the hES-EC+MC-injected group (14.7 ± 0.6%) was markedly higher compared to those in the other four groups (P < 0.001 vs control, P < 0.01 vs hES-ECs, P < 0.05 vs hES-MCs) (Figure 5C).

Bottom Line: We examined the potential of vascular cells derived from human ES cells to contribute to vascular regeneration and to provide therapeutic benefit for the ischemic brain.Transplanted ECs were successfully incorporated into host capillaries and MCs were distributed in the areas surrounding endothelial tubes.Transplantation of ECs and MCs derived from undifferentiated human ES cells have a potential to contribute to therapeutic vascular regeneration and consequently reduction of infarct area after stroke.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Medicine and Clinical Science, Kyoto University Graduate School of Medicine, Kyoto, Japan. kanu@kuhp.kyoto-u.ac.jp

ABSTRACT

Background: We previously demonstrated that vascular endothelial growth factor receptor type 2 (VEGF-R2)-positive cells induced from mouse embryonic stem (ES) cells can differentiate into both endothelial cells (ECs) and mural cells (MCs) and these vascular cells construct blood vessel structures in vitro. Recently, we have also established a method for the large-scale expansion of ECs and MCs derived from human ES cells. We examined the potential of vascular cells derived from human ES cells to contribute to vascular regeneration and to provide therapeutic benefit for the ischemic brain.

Methods: Phosphate buffered saline, human peripheral blood mononuclear cells (hMNCs), ECs-, MCs-, or the mixture of ECs and MCs derived from human ES cells were intra-arterially transplanted into mice after transient middle cerebral artery occlusion (MCAo).

Results: Transplanted ECs were successfully incorporated into host capillaries and MCs were distributed in the areas surrounding endothelial tubes. The cerebral blood flow and the vascular density in the ischemic striatum on day 28 after MCAo had significantly improved in ECs-, MCs- and ECs+MCs-transplanted mice compared to that of mice injected with saline or transplanted with hMNCs. Moreover, compared to saline-injected or hMNC-transplanted mice, significant reduction of the infarct volume and of apoptosis as well as acceleration of neurological recovery were observed on day 28 after MCAo in the cell mixture-transplanted mice.

Conclusion: Transplantation of ECs and MCs derived from undifferentiated human ES cells have a potential to contribute to therapeutic vascular regeneration and consequently reduction of infarct area after stroke.

Show MeSH
Related in: MedlinePlus