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Stem Cell Reports
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Mar 10, 2015

Volume 4Issue 3p313-530
Open Access
Cover The cover is a high-magnification representation of an engineered segment of stem-cell-derived airway epithelial tissue. Shojaie et al., pp. 419–430, report that extended culture of embryonic-stem-cell-derived definitive endodermal cells on decellularized lung scaffolds in defined, serum-free medium promotes differentiation into mature airway epithelial cells. Differentiated cells contain morphological and functional similarities to native ciliated and secretory airway cells. These findings provide evidence for the robust inductive capacity of the native lung matrix alone. The image is a representation of the surface of differentiated airway cultures generated using scanning electron microscopy. Faux coloring of the micrograph is used to distinguish tight-junction-coupled ciliated cells, in green, from nonciliated cells, in pink. Intermediary ciliated cells are shown in blue and orange....
Cover The cover is a high-magnification representation of an engineered segment of stem-cell-derived airway epithelial tissue. Shojaie et al., pp. 419–430, report that extended culture of embryonic-stem-cell-derived definitive endodermal cells on decellularized lung scaffolds in defined, serum-free medium promotes differentiation into mature airway epithelial cells. Differentiated cells contain morphological and functional similarities to native ciliated and secretory airway cells. These findings provide evidence for the robust inductive capacity of the native lung matrix alone. The image is a representation of the surface of differentiated airway cultures generated using scanning electron microscopy. Faux coloring of the micrograph is used to distinguish tight-junction-coupled ciliated cells, in green, from nonciliated cells, in pink. Intermediary ciliated cells are shown in blue and orange.
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Reports

  • A Progesterone-CXCR4 Axis Controls Mammary Progenitor Cell Fate in the Adult Gland

    • Yu-Jia Shiah,
    • Pirashaanthy Tharmapalan,
    • Alison E. Casey,
    • Purna A. Joshi,
    • Trevor D. McKee,
    • Hartland W. Jackson,
    • Alexander G. Beristain,
    • Michelle A. Chan-Seng-Yue,
    • Gary D. Bader,
    • John P. Lydon,
    • Paul D. Waterhouse,
    • Paul C. Boutros,
    • Rama Khokha
    In this article, Khokha and colleagues use expression profiling and functional assays to identify CXCR4, the receptor for stromal-derived factor 1 (SDF-1; CXC12), as a crucial instructor of hormone-induced mammary stem and progenitor cell function. Pharmacological inhibition of CXCR4 signaling abrogates progesterone-directed expansion of basal and luminal subsets, resulting in a marked reduction in CD49b+SCA-1− luminal progenitors and their functional capacity, and lobuloalveologenesis.

  • A Transposon-Mediated System for Flexible Control of Transgene Expression in Stem and Progenitor-Derived Lineages

    • Aslam Abbasi Akhtar,
    • Jessica Molina,
    • Marina Dutra-Clarke,
    • Gi Bum Kim,
    • Rachelle Levy,
    • William Schreiber-Stainthorp,
    • Moise Danielpour,
    • Joshua J. Breunig
    In this article, Breunig and colleagues describe a stable, flexible genetic system for inducible and reversible gene expression. The doxycycline-mediated system, termed pB-Tet-GOI, is non-leaky, robust, and allows for “On→Off→On,” “Off→On→Off” and inducible-constitutive temporal control (“Off→permanently On”) of transgenes in vivo and in vitro, as well as a dox-resistant variant for strong, constitutive expression of transgenes.

  • In Vivo Therapeutic Potential of Mesenchymal Stromal Cells Depends on the Source and the Isolation Procedure

    • Francesca Bortolotti,
    • Laura Ukovich,
    • Vahid Razban,
    • Valentina Martinelli,
    • Giulia Ruozi,
    • Barbara Pelos,
    • Franca Dore,
    • Mauro Giacca,
    • Serena Zacchigna
    Zacchigna and colleagues compared the ex vivo and in vivo properties of mesenchymal stromal cells (MSCs) isolated from either adipose tissue or bone marrow by different protocols. Adhesive MSCs from bone marrow exerted the best therapeutic activity in a hindlimb ischemia model, preserving viability and inducing angiogenesis in a paracrine manner. The optimization of a standard MSC isolation procedure is required to improve clinical results.

  • Structural Phenotyping of Stem Cell-Derived Cardiomyocytes

    • Francesco Silvio Pasqualini,
    • Sean Paul Sheehy,
    • Ashutosh Agarwal,
    • Yvonne Aratyn-Schaus,
    • Kevin Kit Parker
    In this article, Parker and colleagues develop metrics to quantitatively characterize myofibrillogenesis and sarcomerogenesis, the processes by which striated muscle cells assemble their contractile cytoskeleton. Further, they coupled these metrics with machine-learning algorithms to unbiasedly score the phenotypic maturity of primary and stem cell-derived cardiomyocytes.

Articles

  • Human iPSC-Derived Hepatocyte-like Cells Support Plasmodium Liver-Stage Infection In Vitro

    • Shengyong Ng,
    • Robert E. Schwartz,
    • Sandra March,
    • Ani Galstian,
    • Nil Gural,
    • Jing Shan,
    • Mythili Prabhu,
    • Maria M. Mota,
    • Sangeeta N. Bhatia
    In this article, Bhatia and colleagues show that iPSC-derived hepatocyte-like cells (iHLCs) can be infected with Plasmodium parasites of the species that cause human malaria, starting from the hepatoblast stage. They also demonstrate that further maturation of iHLCs by small molecules confers drug sensitivity to a model antimalarial, primaquine, that requires hepatic bioactivation.

  • Long-Term Safety Issues of iPSC-Based Cell Therapy in a Spinal Cord Injury Model: Oncogenic Transformation with Epithelial-Mesenchymal Transition

    • Satoshi Nori,
    • Yohei Okada,
    • Soraya Nishimura,
    • Takashi Sasaki,
    • Go Itakura,
    • Yoshiomi Kobayashi,
    • Francois Renault-Mihara,
    • Atsushi Shimizu,
    • Ikuko Koya,
    • Rei Yoshida,
    • Jun Kudoh,
    • Masato Koike,
    • Yasuo Uchiyama,
    • Eiji Ikeda,
    • Yoshiaki Toyama,
    • Masaya Nakamura,
    • Hideyuki Okano
    Previously, Okano and colleagues reported the therapeutic potential of induced pluripotent stem cell (iPSC)-derived neurospheres for spinal cord injury. However, safety issues concerning iPSC-based therapy remain unresolved. In this article, they show that grafted human iPSC (253G1)-derived neurospheres formed undifferentiated neural tumors after long-term observation. The tumors exhibited activation of the OCT4 transgene and a heightened mesenchymal transition. Integration-free iPSCs should be chosen to avoid transgene-induced tumorigenesis.

  • CDK1 Inhibition Targets the p53-NOXA-MCL1 Axis, Selectively Kills Embryonic Stem Cells, and Prevents Teratoma Formation

    • Noelle E. Huskey,
    • Tingxia Guo,
    • Kimberley J. Evason,
    • Olga Momcilovic,
    • David Pardo,
    • Katelyn J. Creasman,
    • Robert L. Judson,
    • Robert Blelloch,
    • Scott A. Oakes,
    • Matthias Hebrok,
    • Andrei Goga
    In this article, Goga and colleagues show that mouse and human embryonic stem cells (ESCs) are uniquely sensitive to Cdk1 inhibition. Treatment of ESCs with Cdk1 inhibitors results in p53 activation, upregulation of Noxa, negative regulation of Mcl1, and apoptosis. Cdk1 inhibitors deplete undifferentiated stem cells from a heterogeneous cell population and prevent stem cell-driven tumors in vivo.

  • The BET Family Member BRD4 Interacts with OCT4 and Regulates Pluripotency Gene Expression

    • Tao Wu,
    • Hugo Borges Pinto,
    • Yasunao F. Kamikawa,
    • Mary E. Donohoe
    OCT4 is a master regulator of pluripotency in embryonic stem cells (ESCs). In this article, Donohoe and colleagues show that OCT4 interacts with the BET family member BRD4. BRD4 occupies the genes controlling pluripotency, and the long noncoding RNAs regulating female X chromosome inactivation. Inhibition or loss of BRD4 shifts ESC fate from pluripotency to neuroectoderm. Inhibition of the BRD4 partner P-TEFb blocks gene activity in ESCs. BRD4 is pivotal for gene transcription in ESCs.

  • Generation of Scaffoldless Hyaline Cartilaginous Tissue from Human iPSCs

    • Akihiro Yamashita,
    • Miho Morioka,
    • Yasuhito Yahara,
    • Minoru Okada,
    • Tomohito Kobayashi,
    • Shinichi Kuriyama,
    • Shuichi Matsuda,
    • Noriyuki Tsumaki
    In this article, Tsumaki and colleagues generated particles of scaffoldless hyaline cartilage from hiPSCs. They used a chondrocyte-specific monitoring system to optimize the culture conditions and three-dimensional suspension culture in their approach. The hiPSC-derived cartilaginous particles had the potential to fix articular cartilage defects without forming tumors or ectopic tissue when transplanted into model animals including mice, rats, and mini-pigs.

  • Acellular Lung Scaffolds Direct Differentiation of Endoderm to Functional Airway Epithelial Cells: Requirement of Matrix-Bound HS Proteoglycans

    • Sharareh Shojaie,
    • Leonardo Ermini,
    • Cameron Ackerley,
    • Jinxia Wang,
    • Stephanie Chin,
    • Behzad Yeganeh,
    • Mélanie Bilodeau,
    • Manpreet Sambi,
    • Ian Rogers,
    • Janet Rossant,
    • Christine E. Bear,
    • Martin Post
    In this article, Post and colleagues have demonstrated that functional airway epithelial cells (ciliated, club, and basal cells) can be generated from murine ESCs by culturing endoderm-induced cells on decellularized lung scaffolds without additional serum and growth factor supplementation. This differentiation was found to be dependent on heparan sulfate proteoglycans present on lung scaffolds.

  • In Vivo Repopulating Activity Emerges at the Onset of Hematopoietic Specification during Embryonic Stem Cell Differentiation

    • Stella Pearson,
    • Sara Cuvertino,
    • Maud Fleury,
    • Georges Lacaud,
    • Valerie Kouskoff
    In this article, Kouskoff, Lacaud, and colleagues show that serum-free in vitro differentiated embryonic stem cells give rise to in vivo repopulating hematopoietic progenitors, that the repopulating activity arises immediately upon the commitment of mesodermal precursors to the blood program, and that the formation of these progenitors is extremely transient and exquisitely sensitive to the cytokine milieu.

  • Enhanced Hematopoietic Stem Cell Function Mediates Immune Regeneration following Sex Steroid Blockade

    • Danika M. Khong,
    • Jarrod A. Dudakov,
    • Maree V. Hammett,
    • Marc I. Jurblum,
    • Sacha M.L. Khong,
    • Gabrielle L. Goldberg,
    • Tomoo Ueno,
    • Lisa Spyroglou,
    • Lauren F. Young,
    • Marcel R.M. van den Brink,
    • Richard L. Boyd,
    • Ann P. Chidgey
    Age-related declines in immune function underlie a wide range of diseases and impaired capacity to recover adaptive immunity following therapeutic immune depletion. Increasing evidence implicates a functional decline in hematopoietic stem cells (HSCs). Here, Chidgey, Dudakov, and colleagues demonstrate that reversal of HSC aging by blocking the immunosuppressive actions of sex steroids involves mechanisms both intrinsic and extrinsic to HSCs. These findings will enable progress in understanding bone marrow and HSC aging and in developing strategies for immune regeneration.

  • Long-Term Expansion, Enhanced Chondrogenic Potential, and Suppression of Endochondral Ossification of Adult Human MSCs via WNT Signaling Modulation

    • Roberto Narcisi,
    • Mairéad A. Cleary,
    • Pieter A.J. Brama,
    • Martin J. Hoogduijn,
    • Nesrin Tüysüz,
    • Derk ten Berge,
    • Gerjo J.V.M. van Osch
    van Osch, ten Berge, and colleagues show that the signaling protein WNT3A, in combination with FGF2, supports long-term expansion and enhances the chondrogenic capacity of human bone marrow-derived MSCs. Moreover, inhibition of WNT signals during differentiation prevents hypertrophic maturation and calcification in vivo, until now one of the major obstacles in the use of MSCs for cartilage repair.

  • Comparative Quantification of the Surfaceome of Human Multipotent Mesenchymal Progenitor Cells

    • Rebecca J. Holley,
    • Guangping Tai,
    • Andrew J.K. Williamson,
    • Samuel Taylor,
    • Stuart A. Cain,
    • Stephen M. Richardson,
    • Catherine L.R. Merry,
    • Anthony D. Whetton,
    • Cay M. Kielty,
    • Ann E. Canfield
    In this article, Canfield, Kielty, and colleagues utilized subcellular fractionation with quantitative discovery proteomics to define the cell-matrix interface of human mesenchymal progenitor cells from bone marrow and umbilical cord. They identified 186 upregulated mesenchymal progenitor biomarkers and how some of these markers influence cell fate. This comprehensive cell-surface marker repository enables improved characterization of progenitor populations.

  • Functional Differences between GDNF-Dependent and FGF2-Dependent Mouse Spermatogonial Stem Cell Self-Renewal

    • Seiji Takashima,
    • Mito Kanatsu-Shinohara,
    • Takashi Tanaka,
    • Hiroko Morimoto,
    • Kimiko Inoue,
    • Narumi Ogonuki,
    • Mayumi Jijiwa,
    • Masahide Takahashi,
    • Atsuo Ogura,
    • Takashi Shinohara
    In this article, Shinohara and colleagues show that spermatogonial stem cells (SSCs) undergo at least two types of self-renewal. GDNF is thought to be indispensable for SSC survival and self-renewal. However, the authors analyzed Ret mutant mice and found that SSCs undergo self-renewal without GDNF. SSC self-renewal was recapitulated in vitro without GDNF.

Resources

  • Defined Conditions for the Isolation and Expansion of Basal Prostate Progenitor Cells of Mouse and Human Origin

    • Thomas Höfner,
    • Christian Eisen,
    • Corinna Klein,
    • Teresa Rigo-Watermeier,
    • Stephan M. Goeppinger,
    • Anna Jauch,
    • Brigitte Schoell,
    • Vanessa Vogel,
    • Elisa Noll,
    • Wilko Weichert,
    • Irène Baccelli,
    • Anja Schillert,
    • Steve Wagner,
    • Sascha Pahernik,
    • Martin R. Sprick,
    • Andreas Trumpp
    Trumpp, Sprick, and colleagues describe a method that enables efficient isolation and in vitro expansion of primary human and mouse prostate epithelial stem/progenitor cells (PESCs). The utility of this method for discovering novel markers and functional pathways important for prostate biology is demonstrated by the identification and functional verification of the involvement of NF-kB signaling during differentiation of PESCs.

  • The L1TD1 Protein Interactome Reveals the Importance of Post-transcriptional Regulation in Human Pluripotency

    • Maheswara Reddy Emani,
    • Elisa Närvä,
    • Aki Stubb,
    • Deepankar Chakroborty,
    • Miro Viitala,
    • Anne Rokka,
    • Nelly Rahkonen,
    • Robert Moulder,
    • Konstantin Denessiouk,
    • Ras Trokovic,
    • Riikka Lund,
    • Laura L. Elo,
    • Riitta Lahesmaa
    In this work, Lahesmaa and colleagues constructed a protein interactome of a highly stem-cell-specific RNA-binding protein, L1TD1, in human embryonic stem cells. The L1TD1 interactome reveals uncharacterized factors that share the same network with OCT4, SOX2, and NANOG. In addition, the data show that RNA-binding proteins have an important role in the regulation of pluripotency.

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