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First published online September 11, 2008
Stem Cells Vol. 26 No. 12 December 2008, pp. 3205 -3209
Evidence That an Early Pregnancy Causes a Persistent Decrease in the Number of Functional Mammary Epithelial Stem Cells—Implications for Pregnancy-Induced Protection Against Breast Cancer
[Stefan K. Siwkoa, Jie Donga, Michael T. Lewisa, Hao Liub, Susan G. Hilsenbecka, Yi Lia,c]

aThe Lester and Sue Smith Breast Center,
bDivision of Biostatistics, Dan L. Duncan Cancer Center, and
cDepartment of Molecular and Cell Biology, Baylor College of Medicine, Houston, Texas, USA

Key Words. Epithelial cells • Mammary glands • Pregnancy • Stem cells • Stem cell transplantation

Correspondence: Correspondence: Yi Li, Ph.D., One Baylor Plaza BCM 600, Houston, Texas 77030, USA. Telephone: 713-798-3963; Fax: 713-798-1659; e-mail: [email protected]

Received on February 4, 2008; accepted for publication on September 3, 2008.

First published online in STEM CELLS EXPRESS  September 11, 2008.

A completed pregnancy at a young age reduces a woman's lifetime risk of breast cancer by up to 50%. A similar protective effect of an early pregnancy has been observed in rodent models using chemical carcinogens. However, the mechanisms responsible for this protective effect remain unclear. Stem cells have been proposed to be the cells of origin for breast cancer. We hypothesized that an early pregnancy reduces adult levels of either mammary stem cells or mammary multipotent progenitor cells. Unsorted mammary cells from adult mice that had undergone an early parity had the same mammosphere formation efficiency as cells from age-matched virgin mice. However, when we transplanted adult mammary cells in limiting dilutions into cleared fat pads of syngeneic mice, we found a significant reduction in the outgrowth potential of the cells from early parous mice compared with age-matched virgin mice. The extent of fat pad filling in successful outgrowths did not change, suggesting that although mammary stem cells in parous mice retained their functional competence, the number of mammary stem cells was reduced. Our results provide the first direct evidence that an early pregnancy has an effect on mammary stem cells.

Disclosure of potential conflicts of interest is found at the end of this article.

First published online October 23, 2008
Stem Cells Vol. 27 No. 1 January 2009, pp. 40 -48
Cancer Stem Cells
SOX2 Silencing in Glioblastoma Tumor-Initiating Cells Causes Stop of Proliferation and Loss of Tumorigenicity

Rosaria Maria Rita Gangemia, Fabrizio Grifferoa,b, Daniela Marubbia,b, Marzia Pereraa, Maria Cristina Capraa, Paolo Malatestaa,b, Gian Luigi Ravettic, Gian Luigi Zonad, Antonio Dagaa, Giorgio Cortea,b

aIstituto Nazionale per la Ricerca sul Cancro, Genova, Italy
bDipartimento di Oncologia Biologia e Genetica, Università di Genova, Genova, Italy
cAnatomia Patologica Ospedaliera, Ospedale S. Martino, Università di Genova, Genova, Italy
dDipartimento di Neuroscienze, Oftalmologia e Genetica, Università di Genova, Genova, Italy

Key Words. Glioblastoma • Tumor-initiating cells • SOX2 gene silencing • Tumorigenesis

Correspondence: Istituto Nazionale per la Ricerca sul Cancro, Largo R. Benzi 10, 16132 Genova, Italy. Telephone: 39-010-5737404; Fax: 39-010-5737405; e-mail: [email protected]

Received on May 20, 2008; accepted for publication on October 10, 2008.

First published online in STEM CELLS EXPRESS  October 23, 2008.

Glioblastoma, the most aggressive cerebral tumor, is invariably lethal. Glioblastoma cells express several genes typical of normal neural stem cells. One of them, SOX2, is a master gene involved in sustaining self-renewal of several stem cells, in particular neural stem cells. To investigate its role in the aberrant growth of glioblastoma, we silenced SOX2 in freshly derived glioblastoma tumor-initiating cells (TICs). Our results indicate that SOX2 silenced glioblastoma TICs, despite the many mutations they have accumulated, stop proliferating and lose tumorigenicity in immunodeficient mice. SOX2 is then also fundamental for maintenance of the self-renewal capacity of neural stem cells when they have acquired cancer properties. SOX2, or its immediate downstream effectors, would then be an ideal target for glioblastoma therapy. STEM CELLS 2009;27:40–48

First published online November 26, 2008
Stem Cells Vol. 27 No. 2 February 2009, pp. 457 -466
Translational and Clinical Research
CD133 Progenitor Cells from the Bone Marrow Contribute to Retinal Pigment Epithelium Repair

[Jeffrey R. Harrisa, Robert Fishera, Marda Jorgensena, Shalesh Kaushala, Edward W. Scotta]

Program in Stem Cell Biology, McKnight Brain Institute, University of Florida, Gainesville, Florida, USA
Correspondence: Program in Stem Cell Biology and Regenerative Medicine, University of Florida, Box 100201, 1600 SW Archer Road, Gainesville, Florida 32610, USA. Telephone: 352-846-1149; Fax: 352-392-5802; e-mail: [email protected]

Received on August 25, 2008; accepted for publication on November 5, 2008.

First published online in STEM CELLS EXPRESS  November 26, 2008.

Our goal was to define a clinically significant population of cells by utilizing a single-step selection process to enrich hematopoietic cells capable of regenerating the retinal pigment epithelium (RPE). Utilizing intravitreal injection of bone marrow cells from a mouse with pigment (C57BL6:gfp) into albino recipient mice (C57BL6:Tyr-), we show that hematopoietic progenitor cells (HPCs) enriched for CD133 can regenerate RPE cells and improve retinal function. The chemokine CXCL12 (stromal cell-derived factor 1{alpha}) is essential for migration, incorporation, and RPE regeneration by CD133+ HPCs. Once incorporated, CD133+ HPCs become pigmented, adopt an RPE morphology, and express RPE-specific proteins, leading to partial functional recovery by electroretinogram. Human CD133+ HPCs also incorporate in the retina and assume RPE morphology in nonobese diabetic/severe combined immunodeficient mice xenografts. These data show that a clinically accessible CD133+ hematopoietic cell can home to an injured RPE layer, differentiate into cells with significant RPE morphology, and provide therapeutic functional recovery of the visual cycle. STEM CELLS 2009;27:457–466

First published online November 26, 2008
Stem Cells Vol. 27 No. 2 February 2009, pp. 399 -407

Tissue-Specific Stem Cells
Diabetes Impairs the Vascular Recruitment of Normal Stem Cells by Oxidant Damage, Reversed by Increases in pAMPK, Heme Oxygenase-1, and Adiponectin

[Gianmario Sambucetia,b, Silvia Morbellia, Luca Vanellac, Claudia Kusmicd, Cecilia Marinid, Michela Massolloa, Carla Augeria, Mirko Corsellie, Chiara Ghersia, Barbara Chiavarinae, Luigi F. Rodellag, Antonio L'Abbatef, George Drummondc, Nader G. Abrahamc, Francesco Frassonie]

Key Words. Endothelial progenitor cells • NO • pAMPK • HO-1 • Vascular repair • CD31

Correspondence: University of Genoa, Largo R. Benzi, 1016132 Genova, Italy. Teleph

one: 914-594-4132; Fax: 914-594-4119; e-mail: [email protected], [email protected]

Correspondence: New York Medical College, Valhalla, New York 10595, USA

Received on August 14, 2008; accepted for publication on October 19, 2008.

First published online in STEM CELLS EXPRESS  November 26, 2008.

Background: Atherosclerosis progression is accelerated in diabetes mellitus (DM) by either direct endothelial damage or reduced availability and function of endothelial progenitor cells (EPCs). Both alterations are related to increased oxidant damage.

Aim: We examined if DM specifically impairs vascular signaling, thereby reducing the recruitment of normal EPCs, and if increases in antioxidant levels by induction of heme oxygenase-1 (HO-1) can reverse this condition.

Methods: Control and diabetic rats were treated with the HO-1 inducer cobalt protoporphyrin (CoPP) once a week for 3 weeks. Eight weeks after the development of diabetes, EPCs harvested from the aorta of syngenic inbred normal rats and labeled with technetium-99m-exametazime were infused via the femoral vein to estimate their blood clearance and aortic recruitment. Circulating endothelial cells (CECs) and the aortic expression of thrombomodulin (TM), CD31, and endothelial nitric oxide synthase (eNOS) were used to measure endothelial damage.

Results: DM reduced blood clearance and aortic recruitment of EPCs. Both parameters were returned to control levels by CoPP treatment without affecting EPC kinetics in normal animals. These abnormalities of EPCs in DM were paralleled by reduced serum adiponectin levels, increased numbers of CECs, reduced endothelial expression of phosphorylated eNOS, and reduced levels of TM, CD31, and phosphorylated AMP-activated protein kinase (pAMPK). CoPP treatment restored all of these parameters to normal levels.

Conclusion: Type II DM and its related oxidant damage hamper the interaction between the vascular wall and normal EPCs by mechanisms that are, at least partially, reversed by the induction of HO-1 gene expression, adiponectin, and pAMPK levels. STEM CELLS 2009;27:399–407

Tissue-Specific Stem Cells
Specific Lineage-Priming of Bone Marrow Mesenchymal Stem Cells Provides the Molecular Framework for Their Plasticity

Bruno Delorme 1 2, Jochen Ringe 3, Charalampos Pontikoglou 1, Julien Gaillard 1 4, Alain Langonné 1 4, Luc Sensebé 1 4, Danièle Noël 5, Christian Jorgensen 5, Thomas Häupl 3, Pierre Charbord 1 6 *§
1Institut National de la Recherche et Santé Médicale (INSERM), Equipe ESPRI/EA-3855, University François Rabelais, Faculty of Medicine, Tours, France
2MacoPharma, Tourcoing, France
3Department of Rheumatology and Clinical Immunology, Laboratory for Tissue Engineering, Charité-University Medicine, Berlin, Germany
4Etablissement Français du Sang-Centre-Atlantique, Tours, France
5INSERM, U844, Lapeyronie Hospital, Montpellier, France
6INSERM, U972, Paul Brousse Hospital, Villejuif, France
email: Pierre Charbord ([email protected])

*Correspondence to Pierre Charbord, INSERM U972, Batiment Lavoisier, Hôpital Paul Brousse, 14-16 Av Paul-Vaillant Couturier, Villejuif 94807, France
Author contributions: P.C., B.D., T.H., C.J.: conception and design; P.C., L.S., T.H.: financial support; L.S.: provision of study material; B.D., J.R., C.P., G.J., A.L., D.N.: collection of data; B.D., P.C., T.H.: data analysis and interpretation; P.C., B.D., T.H.: manuscript writing; P.C., T.H.: final approval.
First published online in Stem CellsExpress February 12, 2009
§Telephone: 33 1 8696 2759; Fax: 33 1 4559 5268

Differentiation • Osteoblast • Chondrocyte • Adipocyte • Muscle • Neuron • Hepatocyte • Endothelium

Lineage-priming is a molecular model of stem cell (SC) differentiation in which proliferating SCs express a subset of genes associated to the differentiation pathways to which they can commit. This concept has been developed for hematopoietic SCs, but has been poorly studied for other SC populations. Because the differentiation potential of human bone marrow mesenchymal stem cells (BM MSCs) remains controversial, we have explored the theory of lineage-priming applied to these cells. We show that proliferating primary layers and clones of BM MSCs have precise priming to the osteoblastic (O), chondrocytic (C), adipocytic (A), and the vascular smooth muscle (V) lineages, but not to skeletal muscle, cardiac muscle, hematopoietic, hepatocytic, or neural lineages. Priming was shown both at the mRNA (300 transcripts were evaluated) and the protein level. In particular, the master transactivator proteins PPARG, RUNX2, and SOX9 were coexpressed before differentiation induction in all cells from incipient clones. We further show that MSCs cultured in the presence of inducers differentiate into the lineages for which they are primed. Our data point out to a number of signaling pathways that might be activated in proliferating MSCs and would be responsible for the differentiation and proliferation potential of these cells. Our results extend the notion of lineage-priming and provide the molecular framework for inter-A, -O, -C, -V plasticity of BM MSCs. Our data highlight the use of BM MSCs for the cell therapy of skeletal or vascular disorders, but provide a word of caution about their use in other clinical indications. Stem Cells 2009;27:1142-1151
Received: 27 October 2008; Accepted: 24 January 2009

Digital Object Identifier (DOI)

10.1002/stem.34  About DOI

Tissue-Specific Stem Cells
Precursors with Glial Fibrillary Acidic Protein Promoter Activity Transiently Generate GABA Interneurons in the Postnatal Cerebellum

John Silbereis 1, Elise Cheng 1, Yosif M. Ganat 1, Laura R. Ment 2, Flora M. Vaccarino 1 3 *§
1Child Study Center, Yale University School of Medicine, New Haven, Connecticut, USA
2Department of Pediatrics, Yale University School of Medicine, New Haven, Connecticut, USA
3Department of Neurobiology, Yale University School of Medicine, New Haven, Connecticut, USA
email: Flora M. Vaccarino ([email protected])

*Correspondence to Flora M. Vaccarino, Child Study Center, Yale University, 230 South Frontage Rd, New Haven, CT 06520, USA
Author contributions: J.S.: conception and design, collection and/or assembly of data, data analysis and interpretation, manuscript writing, final approval of manuscript; E.C.: collection and/or assembly of data, data analysis and interpretation, final approval of manuscript; Y.M.G.: conception and design, collection and/or assembly of data, data analysis and interpretation, final approval of manuscript; L.R.M.: manuscript writing, financial support, final approval of manuscript; F.M.V.: conception and design, collection and/or assembly of data, data analysis and interpretation, manuscript writing, financial support, final approval of manuscript.
First published online in Stem CellsExpress January 29, 2009
§Telephone: 203-737-4147; Fax: 203-737-3524

Cerebellum • Astrocytes • Neural stem cells • Neural differentiation • Progenitor cell • Tissue specific stem cell • Transgenic mouse • GABA interneurons

Neural stem or progenitor cells (NSC/NPCs) able to generate the different neuron and glial cell types of the cerebellum have been isolated in vitro, but their identity and location in the intact cerebellum are unclear. Here, we use inducible Cre recombination in GFAPCreERT2 mice to irreversibly activate reporter gene expression at P2 (postnatal day 2), P5, and P12 in cells with GFAP (glial fibrillary acidic protein) promoter activi

ty and analyze the fate of genetically tagged cells in vivo. We show that cells tagged at P2-P5 with -galactosidase or enhanced green fluorescent proteins reporter genes generate at least 30% of basket and stellate GABAergic interneurons in the molecular layer (ML) and that they lose their neurogenic potential by P12, after which they generate only glia. Tagged cells in the cerebellar white matter (WM) were initially GFAP/S100+ and expressed the NSC/NPCs proteins LeX, Musashi1, and Sox2 in vivo. One week after tagging, reporter+ cells in the WM upregulated the neuronal progenitor markers Mash1, Pax2, and Gad-67. These Pax2+ progenitors migrated throughout the cerebellar cortex, populating the ML and leaving the WM by P18. These data suggest that a pool of GFAP/S100+ glial cells located in the cerebellar WM generate a large fraction of cerebellar interneurons for the ML within the first postnatal 12 days of cerebellar development. This restricted critical period implies that powerful inhibitory factors may restrict their fate potential in vivo at later stages of development. Stem Cells 2009;27:1152-1163
Received: 9 September 2008; Accepted: 19 January 2009

Digital Object Identifier (DOI)
10.1002/stem.18  About DOI