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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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Transplantation of adult NSCs into the pancreasAdult HPC NSCs grafted into pancreas express insulin. IHC of tracing Sox2CreGFP cells. In control NSCs transplantation (Control NSC TP), Sox2CreGFP+ cells co-localized with insulin.Adult HPC NSCs grafted into pancreas express insulin. IHC of tracing Sox2CreGFP cells. In β-catenin cKO NSCs transplantation (β-catenin cKO NSC TP), Sox2CreGFP+ cells were insulin-negative. Cells in the white square region are magnified and shown in separate panels at right. Insulin, red; Sox2CreGFP, green; DAPI, blue.Detection of MafA-positive cells in grafted adult HPC NSCs into pancreas. IHC of MafA and Sox2CreGFP in control NSC TP is shown. MafA, red; Sox2CreGFP, green; DAPI, blue.Ptf1a-expressing cells in grafted adult HPC NSCs into pancreas. Ptf1a, red; Sox2CreGFP, green; DAPI, blue.IHC of tracing Sox2CreGFP cells in β-catenin cKO NSC TP. The β-catenin cKO NSCs remained in the nestin+ progenitor stage. Nestin, red; Sox2CreGFP, green; DAPI, blue.Numbers of GFP+ cells in the pancreas of control TP mice (white bars) and β-catenin cKO NSC TP mice (black bars).The phenotypic characterization of the grafted adult NSCs of control TP mice and β-catenin cKO NSC TP mice.Numbers of marker and GFP double-positive cells in the grafted pancreas of control TP mice and β-catenin cKO NSC TP mice.Percentages of BrdU and GFP double-positive cells in the grafted pancreas of control TP mice and β-catenin cKO NSC TP mice.Numbers of AC3 and GFP double-positive cells in the grafted pancreas of control TP mice and β-catenin cKO NSC TP mice.
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fig04: Transplantation of adult NSCs into the pancreasAdult HPC NSCs grafted into pancreas express insulin. IHC of tracing Sox2CreGFP cells. In control NSCs transplantation (Control NSC TP), Sox2CreGFP+ cells co-localized with insulin.Adult HPC NSCs grafted into pancreas express insulin. IHC of tracing Sox2CreGFP cells. In β-catenin cKO NSCs transplantation (β-catenin cKO NSC TP), Sox2CreGFP+ cells were insulin-negative. Cells in the white square region are magnified and shown in separate panels at right. Insulin, red; Sox2CreGFP, green; DAPI, blue.Detection of MafA-positive cells in grafted adult HPC NSCs into pancreas. IHC of MafA and Sox2CreGFP in control NSC TP is shown. MafA, red; Sox2CreGFP, green; DAPI, blue.Ptf1a-expressing cells in grafted adult HPC NSCs into pancreas. Ptf1a, red; Sox2CreGFP, green; DAPI, blue.IHC of tracing Sox2CreGFP cells in β-catenin cKO NSC TP. The β-catenin cKO NSCs remained in the nestin+ progenitor stage. Nestin, red; Sox2CreGFP, green; DAPI, blue.Numbers of GFP+ cells in the pancreas of control TP mice (white bars) and β-catenin cKO NSC TP mice (black bars).The phenotypic characterization of the grafted adult NSCs of control TP mice and β-catenin cKO NSC TP mice.Numbers of marker and GFP double-positive cells in the grafted pancreas of control TP mice and β-catenin cKO NSC TP mice.Percentages of BrdU and GFP double-positive cells in the grafted pancreas of control TP mice and β-catenin cKO NSC TP mice.Numbers of AC3 and GFP double-positive cells in the grafted pancreas of control TP mice and β-catenin cKO NSC TP mice.

Mentions: Adult NSCs were microinjected into adult mouse pancreas. Three weeks later, mice were injected with BrdU daily for 10 days. In the control (Control NSC TP), Sox2CreGFP+ cells co-localized with insulin (Fig 4A), C-peptide (Fig S7B of Supporting information) and NeuroD1 (Fig S7C of Supporting information). Interestingly, we found that Sox2CreGFP+ cells expressed MafA (Fig 4C) and pancreas transcription factor 1a (Ptf1a; Fig 4D). In microarray analysis (Fig 3C), adult NSCs did not express pancreatic β cells markers such as MafA. During embryonic development, lineage commitment of endocrine progenitors requires PTF1a (Kawaguchi et al, 2002). NSCs grafted in the pancreas, expressed β cell-specific markers such as PTF1a and MafA, suggesting that adult NSCs possessed the intrinsic ability to express these β cell-specific markers and that their expression levels were modulated by extracellular factors.


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)

Transplantation of adult NSCs into the pancreasAdult HPC NSCs grafted into pancreas express insulin. IHC of tracing Sox2CreGFP cells. In control NSCs transplantation (Control NSC TP), Sox2CreGFP+ cells co-localized with insulin.Adult HPC NSCs grafted into pancreas express insulin. IHC of tracing Sox2CreGFP cells. In β-catenin cKO NSCs transplantation (β-catenin cKO NSC TP), Sox2CreGFP+ cells were insulin-negative. Cells in the white square region are magnified and shown in separate panels at right. Insulin, red; Sox2CreGFP, green; DAPI, blue.Detection of MafA-positive cells in grafted adult HPC NSCs into pancreas. IHC of MafA and Sox2CreGFP in control NSC TP is shown. MafA, red; Sox2CreGFP, green; DAPI, blue.Ptf1a-expressing cells in grafted adult HPC NSCs into pancreas. Ptf1a, red; Sox2CreGFP, green; DAPI, blue.IHC of tracing Sox2CreGFP cells in β-catenin cKO NSC TP. The β-catenin cKO NSCs remained in the nestin+ progenitor stage. Nestin, red; Sox2CreGFP, green; DAPI, blue.Numbers of GFP+ cells in the pancreas of control TP mice (white bars) and β-catenin cKO NSC TP mice (black bars).The phenotypic characterization of the grafted adult NSCs of control TP mice and β-catenin cKO NSC TP mice.Numbers of marker and GFP double-positive cells in the grafted pancreas of control TP mice and β-catenin cKO NSC TP mice.Percentages of BrdU and GFP double-positive cells in the grafted pancreas of control TP mice and β-catenin cKO NSC TP mice.Numbers of AC3 and GFP double-positive cells in the grafted pancreas of control TP mice and β-catenin cKO NSC TP mice.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3377118&req=5

fig04: Transplantation of adult NSCs into the pancreasAdult HPC NSCs grafted into pancreas express insulin. IHC of tracing Sox2CreGFP cells. In control NSCs transplantation (Control NSC TP), Sox2CreGFP+ cells co-localized with insulin.Adult HPC NSCs grafted into pancreas express insulin. IHC of tracing Sox2CreGFP cells. In β-catenin cKO NSCs transplantation (β-catenin cKO NSC TP), Sox2CreGFP+ cells were insulin-negative. Cells in the white square region are magnified and shown in separate panels at right. Insulin, red; Sox2CreGFP, green; DAPI, blue.Detection of MafA-positive cells in grafted adult HPC NSCs into pancreas. IHC of MafA and Sox2CreGFP in control NSC TP is shown. MafA, red; Sox2CreGFP, green; DAPI, blue.Ptf1a-expressing cells in grafted adult HPC NSCs into pancreas. Ptf1a, red; Sox2CreGFP, green; DAPI, blue.IHC of tracing Sox2CreGFP cells in β-catenin cKO NSC TP. The β-catenin cKO NSCs remained in the nestin+ progenitor stage. Nestin, red; Sox2CreGFP, green; DAPI, blue.Numbers of GFP+ cells in the pancreas of control TP mice (white bars) and β-catenin cKO NSC TP mice (black bars).The phenotypic characterization of the grafted adult NSCs of control TP mice and β-catenin cKO NSC TP mice.Numbers of marker and GFP double-positive cells in the grafted pancreas of control TP mice and β-catenin cKO NSC TP mice.Percentages of BrdU and GFP double-positive cells in the grafted pancreas of control TP mice and β-catenin cKO NSC TP mice.Numbers of AC3 and GFP double-positive cells in the grafted pancreas of control TP mice and β-catenin cKO NSC TP mice.
Mentions: Adult NSCs were microinjected into adult mouse pancreas. Three weeks later, mice were injected with BrdU daily for 10 days. In the control (Control NSC TP), Sox2CreGFP+ cells co-localized with insulin (Fig 4A), C-peptide (Fig S7B of Supporting information) and NeuroD1 (Fig S7C of Supporting information). Interestingly, we found that Sox2CreGFP+ cells expressed MafA (Fig 4C) and pancreas transcription factor 1a (Ptf1a; Fig 4D). In microarray analysis (Fig 3C), adult NSCs did not express pancreatic β cells markers such as MafA. During embryonic development, lineage commitment of endocrine progenitors requires PTF1a (Kawaguchi et al, 2002). NSCs grafted in the pancreas, expressed β cell-specific markers such as PTF1a and MafA, suggesting that adult NSCs possessed the intrinsic ability to express these β cell-specific markers and that their expression levels were modulated by extracellular factors.

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