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Insulin biosynthesis in neuronal progenitors derived from adult hippocampus and the olfactory bulb.

Kuwabara T, Kagalwala MN, Onuma Y, Ito Y, Warashina M, Terashima K, Sanosaka T, Nakashima K, Gage FH, Asashima M - EMBO Mol Med (2011)

Bottom Line: Paracrine Wnt3 plays an essential role in promoting the active expression of insulin in both hippocampal and OB-derived neural stem cells.We also show that adult neural progenitors derived from DB animals retain the ability to give rise to insulin-producing cells and that grafting neuronal progenitors into the pancreas of DB animals reduces glucose levels.This study provides an example of a simple and direct use of adult stem cells from one organ to another, without introducing additional inductive genes.

View Article: PubMed Central - PubMed

Affiliation: Research Center for Stem Cell Engineering, National Institute of Advanced Industrial Science and Technology (AIST), Tsukuba Science City, Japan. t.warashina@aist.go.jp

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Therapeutic treatment of diabetes by adult NSC transplantationInsulin expressions in HPC and OB NSCs derived from DB rats. Insulin promoter activity was measured by using the luciferase reporter construct in adult HPC and OB NSC cultures that were prepared from type II DB rats [GK/slc rats, male; HPC from DB (blue bars) and OB from DB (red bars)]. The effect of Wnt3a ligand and anti-IGFBP-4 on the reporter was assessed in both undifferentiated NSCs and the NP cells. *p < 0.01 and **p < 0.001.The effect of the grafted adult NPs in DB animals. HPC and OB NPs from type II diabetes rats were prepared ex vivo under treatment with Wnt3a and anti-IGFBP-4, and the resultant HPC NP DB and OB NP DB were transplanted into the pancreas of diabetes rats. Open circles, normal rats control; blue squares, HPC NP DB; red squares, OB NP DB; closed circles, diabetes GK/slc rats.IHC of tracing CAG promoter driven EGFP cells (OB NP DB) in type II GK/slc DB rats. Co-localizing cells for insulin and GFP are indicated by white arrows. The preexisting islet expressing insulin at lower levels is indicated by the white arrowhead. Insulin, red; CAG-GFP, green; DAPI, blue.Average of blood glucose levels in the response to intraperitoneal glucose tolerance test. Eighteen weeks after the implantation of adult NPs into rat pancreas, blood glucose levels were measured to glucose administration. Open circles, wild-type rats; blue squares, HPC NP DB grafts into DB rats; red squares, OB NP DB grafts into DB rats; closed circles, GK/Jcl DB rats. n = 4 per each group.IHC of tracing HPC NP DB cells in DB rats. Cells in the white square region are magnified and shown in separate panels at right. Insulin, red; CAG-GFP (GFP), green; BrdU, blue.
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fig05: Therapeutic treatment of diabetes by adult NSC transplantationInsulin expressions in HPC and OB NSCs derived from DB rats. Insulin promoter activity was measured by using the luciferase reporter construct in adult HPC and OB NSC cultures that were prepared from type II DB rats [GK/slc rats, male; HPC from DB (blue bars) and OB from DB (red bars)]. The effect of Wnt3a ligand and anti-IGFBP-4 on the reporter was assessed in both undifferentiated NSCs and the NP cells. *p < 0.01 and **p < 0.001.The effect of the grafted adult NPs in DB animals. HPC and OB NPs from type II diabetes rats were prepared ex vivo under treatment with Wnt3a and anti-IGFBP-4, and the resultant HPC NP DB and OB NP DB were transplanted into the pancreas of diabetes rats. Open circles, normal rats control; blue squares, HPC NP DB; red squares, OB NP DB; closed circles, diabetes GK/slc rats.IHC of tracing CAG promoter driven EGFP cells (OB NP DB) in type II GK/slc DB rats. Co-localizing cells for insulin and GFP are indicated by white arrows. The preexisting islet expressing insulin at lower levels is indicated by the white arrowhead. Insulin, red; CAG-GFP, green; DAPI, blue.Average of blood glucose levels in the response to intraperitoneal glucose tolerance test. Eighteen weeks after the implantation of adult NPs into rat pancreas, blood glucose levels were measured to glucose administration. Open circles, wild-type rats; blue squares, HPC NP DB grafts into DB rats; red squares, OB NP DB grafts into DB rats; closed circles, GK/Jcl DB rats. n = 4 per each group.IHC of tracing HPC NP DB cells in DB rats. Cells in the white square region are magnified and shown in separate panels at right. Insulin, red; CAG-GFP (GFP), green; BrdU, blue.

Mentions: Adult HPC and OB NSCs were prepared from type I (STZ-induced DB rats) and type II DB rats (GK/slc DB rats) and were transplanted back into the pancreases of type I and type II DB rats, respectively. During 2 weeks ex vivo culture of NSCs, insulin expression was examined following Wnt3a and anti-IGFBP-4 addition. Although the HPC of DB animals contained higher IGFBP-4 and lower Wnt3 levels than wild-type (Fig 2D), Wnt3a and anti-IGFBP-4 treatment during the ex vivo culture rescued insulin expression (Fig 5A). These HPC and OB NPs were infected with a retroviral CAG promoter-driven EGFP expression vector to trace the grafted cells (Zhao et al, 2006). GFP+ NPs were transplanted into the pancreas of 8-week-old DB rats. Three to five collagen sheets were stacked and grafted near the splenic lobe among the three pancreatic lobes (i.e. the splenic, gastric and duodenal lobes, n = 8 per group), and blood glucose levels were recorded. Seventeen weeks after the transplantation, rats were injected with BrdU daily for 10 days.


Insulin biosynthesis in neuronal progenitors derived from adult hippocampus and the olfactory bulb.

Kuwabara T, Kagalwala MN, Onuma Y, Ito Y, Warashina M, Terashima K, Sanosaka T, Nakashima K, Gage FH, Asashima M - EMBO Mol Med (2011)

Therapeutic treatment of diabetes by adult NSC transplantationInsulin expressions in HPC and OB NSCs derived from DB rats. Insulin promoter activity was measured by using the luciferase reporter construct in adult HPC and OB NSC cultures that were prepared from type II DB rats [GK/slc rats, male; HPC from DB (blue bars) and OB from DB (red bars)]. The effect of Wnt3a ligand and anti-IGFBP-4 on the reporter was assessed in both undifferentiated NSCs and the NP cells. *p < 0.01 and **p < 0.001.The effect of the grafted adult NPs in DB animals. HPC and OB NPs from type II diabetes rats were prepared ex vivo under treatment with Wnt3a and anti-IGFBP-4, and the resultant HPC NP DB and OB NP DB were transplanted into the pancreas of diabetes rats. Open circles, normal rats control; blue squares, HPC NP DB; red squares, OB NP DB; closed circles, diabetes GK/slc rats.IHC of tracing CAG promoter driven EGFP cells (OB NP DB) in type II GK/slc DB rats. Co-localizing cells for insulin and GFP are indicated by white arrows. The preexisting islet expressing insulin at lower levels is indicated by the white arrowhead. Insulin, red; CAG-GFP, green; DAPI, blue.Average of blood glucose levels in the response to intraperitoneal glucose tolerance test. Eighteen weeks after the implantation of adult NPs into rat pancreas, blood glucose levels were measured to glucose administration. Open circles, wild-type rats; blue squares, HPC NP DB grafts into DB rats; red squares, OB NP DB grafts into DB rats; closed circles, GK/Jcl DB rats. n = 4 per each group.IHC of tracing HPC NP DB cells in DB rats. Cells in the white square region are magnified and shown in separate panels at right. Insulin, red; CAG-GFP (GFP), green; BrdU, blue.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3377118&req=5

fig05: Therapeutic treatment of diabetes by adult NSC transplantationInsulin expressions in HPC and OB NSCs derived from DB rats. Insulin promoter activity was measured by using the luciferase reporter construct in adult HPC and OB NSC cultures that were prepared from type II DB rats [GK/slc rats, male; HPC from DB (blue bars) and OB from DB (red bars)]. The effect of Wnt3a ligand and anti-IGFBP-4 on the reporter was assessed in both undifferentiated NSCs and the NP cells. *p < 0.01 and **p < 0.001.The effect of the grafted adult NPs in DB animals. HPC and OB NPs from type II diabetes rats were prepared ex vivo under treatment with Wnt3a and anti-IGFBP-4, and the resultant HPC NP DB and OB NP DB were transplanted into the pancreas of diabetes rats. Open circles, normal rats control; blue squares, HPC NP DB; red squares, OB NP DB; closed circles, diabetes GK/slc rats.IHC of tracing CAG promoter driven EGFP cells (OB NP DB) in type II GK/slc DB rats. Co-localizing cells for insulin and GFP are indicated by white arrows. The preexisting islet expressing insulin at lower levels is indicated by the white arrowhead. Insulin, red; CAG-GFP, green; DAPI, blue.Average of blood glucose levels in the response to intraperitoneal glucose tolerance test. Eighteen weeks after the implantation of adult NPs into rat pancreas, blood glucose levels were measured to glucose administration. Open circles, wild-type rats; blue squares, HPC NP DB grafts into DB rats; red squares, OB NP DB grafts into DB rats; closed circles, GK/Jcl DB rats. n = 4 per each group.IHC of tracing HPC NP DB cells in DB rats. Cells in the white square region are magnified and shown in separate panels at right. Insulin, red; CAG-GFP (GFP), green; BrdU, blue.
Mentions: Adult HPC and OB NSCs were prepared from type I (STZ-induced DB rats) and type II DB rats (GK/slc DB rats) and were transplanted back into the pancreases of type I and type II DB rats, respectively. During 2 weeks ex vivo culture of NSCs, insulin expression was examined following Wnt3a and anti-IGFBP-4 addition. Although the HPC of DB animals contained higher IGFBP-4 and lower Wnt3 levels than wild-type (Fig 2D), Wnt3a and anti-IGFBP-4 treatment during the ex vivo culture rescued insulin expression (Fig 5A). These HPC and OB NPs were infected with a retroviral CAG promoter-driven EGFP expression vector to trace the grafted cells (Zhao et al, 2006). GFP+ NPs were transplanted into the pancreas of 8-week-old DB rats. Three to five collagen sheets were stacked and grafted near the splenic lobe among the three pancreatic lobes (i.e. the splenic, gastric and duodenal lobes, n = 8 per group), and blood glucose levels were recorded. Seventeen weeks after the transplantation, rats were injected with BrdU daily for 10 days.

Bottom Line: Paracrine Wnt3 plays an essential role in promoting the active expression of insulin in both hippocampal and OB-derived neural stem cells.We also show that adult neural progenitors derived from DB animals retain the ability to give rise to insulin-producing cells and that grafting neuronal progenitors into the pancreas of DB animals reduces glucose levels.This study provides an example of a simple and direct use of adult stem cells from one organ to another, without introducing additional inductive genes.

View Article: PubMed Central - PubMed

Affiliation: Research Center for Stem Cell Engineering, National Institute of Advanced Industrial Science and Technology (AIST), Tsukuba Science City, Japan. t.warashina@aist.go.jp

Show MeSH
Related in: MedlinePlus