Jan 12, 2016

Volume 6Issue 1p1-162
Open Access
Cover The map depicts the two fate choices made by cardiopharyngeal mesoderm (the boat traversing the Mare Mesp1): the second heart field and the facial skeletal muscle progenitor pool. The cloud represents BMP signaling that drives the cardiac fate, while the two sea monsters represent antagonistic signals (TGFβ, the squid; Rho kinase [ROCK], the serpent) that inhibit the derivative cardiac and skeletal muscle lineage differentiation pathways, respectively. See Chan et al., 26–34. The cover image concept was by Sunny Chan, and the artwork was prepared by Cynthia DeKay....
Cover The map depicts the two fate choices made by cardiopharyngeal mesoderm (the boat traversing the Mare Mesp1): the second heart field and the facial skeletal muscle progenitor pool. The cloud represents BMP signaling that drives the cardiac fate, while the two sea monsters represent antagonistic signals (TGFβ, the squid; Rho kinase [ROCK], the serpent) that inhibit the derivative cardiac and skeletal muscle lineage differentiation pathways, respectively. See Chan et al., 26–34. The cover image concept was by Sunny Chan, and the artwork was prepared by Cynthia DeKay.


  • Grafted Human iPS Cell-Derived Oligodendrocyte Precursor Cells Contribute to Robust Remyelination of Demyelinated Axons after Spinal Cord Injury

    • Soya Kawabata,
    • Morito Takano,
    • Yuko Numasawa-Kuroiwa,
    • Go Itakura,
    • Yoshiomi Kobayashi,
    • Yuichiro Nishiyama,
    • Keiko Sugai,
    • Soraya Nishimura,
    • Hiroki Iwai,
    • Miho Isoda,
    • Shinsuke Shibata,
    • Jun Kohyama,
    • Akio Iwanami,
    • Yoshiaki Toyama,
    • Morio Matsumoto,
    • Masaya Nakamura,
    • Hideyuki Okano
    In this article, Okano and colleagues show that the benefits of transplanting human-induced pluripotent stem cell-derived oligodendrocyte precursor cell-enriched neural stem/progenitor cells, describing how this approach contributes to the robust remyelination of demyelinated axons and facilitates functional recovery after spinal cord injury.
  • Xeno-Free and Defined Human Embryonic Stem Cell-Derived Retinal Pigment Epithelial Cells Functionally Integrate in a Large-Eyed Preclinical Model

    • Alvaro Plaza Reyes,
    • Sandra Petrus-Reurer,
    • Liselotte Antonsson,
    • Sonya Stenfelt,
    • Hammurabi Bartuma,
    • Sarita Panula,
    • Theresa Mader,
    • Iyadh Douagi,
    • Helder André,
    • Outi Hovatta,
    • Fredrik Lanner,
    • Anders Kvanta
    Lanner and colleagues present an effective xeno-free and defined hES-RPE cell differentiation methodology using a recombinant human laminin-521 matrix. They further present evidence of long-term functional integration and photoreceptor rescue by transplanted hES-RPE cells in a large-eyed disease model.
  • Directed Induction of Functional Multi-ciliated Cells in Proximal Airway Epithelial Spheroids from Human Pluripotent Stem Cells

    • Satoshi Konishi,
    • Shimpei Gotoh,
    • Kazuhiro Tateishi,
    • Yuki Yamamoto,
    • Yohei Korogi,
    • Tadao Nagasaki,
    • Hisako Matsumoto,
    • Shigeo Muro,
    • Toyohiro Hirai,
    • Isao Ito,
    • Sachiko Tsukita,
    • Michiaki Mishima
    Multi-ciliated airway cells (MCACs) play a crucial role in mucociliary clearance. Gotoh, Konishi, and colleagues demonstrated that three-dimensional (3D) differentiation of CPM+ ventralized anterior foregut endoderm cells is useful for generating proximal airway epithelium, involving functional MCACs as well as pulmonary neuroendocrine cells (PNECs). The induction of MCACs and PNECs was promoted by adding DAPT, a Notch pathway inhibitor.
  • Development of Bipotent Cardiac/Skeletal Myogenic Progenitors from MESP1+ Mesoderm

    • Sunny Sun-Kin Chan,
    • Hannah R. Hagen,
    • Scott A. Swanson,
    • Ron Stewart,
    • Karly A. Boll,
    • Joy Aho,
    • James A. Thomson,
    • Michael Kyba
    In this article, Kyba and colleagues demonstrate that a bipotent PDGFRA+ cardiac/skeletal myogenic progenitor population functionally resembling cardiopharyngeal mesoderm (CPM) can be generated from ES cells differentiated in vitro. They find that TGFβ-BMP and Rho kinase signaling regulate CPM differentiation, and identify PODXL and CDH4 as surface markers for the earliest cardiac and skeletal myogenic-committed progenitors, respectively.
  • Epigenetic Aberrations Are Not Specific to Transcription Factor-Mediated Reprogramming

    • Ulf Tiemann,
    • Guangming Wu,
    • Adele Gabriele Marthaler,
    • Hans Robert Schöler,
    • Natalia Tapia
    Tapia, Schöler, and colleagues converted germline stem cells into pluripotent iPSCs using transcription factors and into pluripotent gPSCs using specific culture conditions. They detected similar levels of donor cell-type memory and reprogramming errors in both pluripotent cell types. These results demonstrate that epigenetic aberrations are not specific to transcription factor-mediated reprogramming.
  • Overcoming Pluripotent Stem Cell Dependence on the Repair of Endogenous DNA Damage

    • Timothy M. Chlon,
    • Sonya Ruiz-Torres,
    • Logan Maag,
    • Christopher N. Mayhew,
    • Kathryn A. Wikenheiser-Brokamp,
    • Stella M. Davies,
    • Parinda Mehta,
    • Kasiani C. Myers,
    • James M. Wells,
    • Susanne I. Wells
    In this article, Wells and colleagues demonstrate that human induced pluripotent stem cell (iPSC) self-renewal is dependent upon the Fanconi anemia DNA repair pathway. FA loss causes iPSC exhaustion, and inhibition of the CHK1 kinase rescues robust, long-term growth of FA-deficient iPSCs, with surprisingly minor karyotypic abnormalities. These findings establish that hyperactive CHK1 signaling ensures highly sensitive genome surveillance in iPSCs.
  • Equine-Induced Pluripotent Stem Cells Retain Lineage Commitment Toward Myogenic and Chondrogenic Fates

    • Mattia Quattrocelli,
    • Giorgia Giacomazzi,
    • Sarah Y. Broeckx,
    • Liesbeth Ceelen,
    • Selin Bolca,
    • Jan H. Spaas,
    • Maurilio Sampaolesi
    The horse industry has a major economic impact worldwide, and needs novel regenerative tools for muscle and cartilage problems. However, a comprehensive strategy for repairing muscle and cartilage is still missing. Equine-induced pluripotent stem cells (iPSCs) have wide potential, but their differentiation toward those tissues remains unaddressed. Furthermore, it is still unknown whether the cell source primes equine iPSCs toward muscle and cartilage differentiation. Sampaolesi, Spaas, and colleagues, by means of isogenic settings and dedicated in vitro assays, report that equine iPSCs retain intrinsic differentiation propensity toward skeletal muscle and cartilage lineages.
  • BMP Sustains Embryonic Stem Cell Self-Renewal through Distinct Functions of Different Krüppel-like Factors

    • Masato Morikawa,
    • Daizo Koinuma,
    • Anna Mizutani,
    • Natsumi Kawasaki,
    • Katarina Holmborn,
    • Anders Sundqvist,
    • Shuichi Tsutsumi,
    • Tetsuro Watabe,
    • Hiroyuki Aburatani,
    • Carl-Henrik Heldin,
    • Kohei Miyazono
    Miyazono, Heldin, and colleagues revisited BMP signaling in a classical model of mouse ESCs. Carrying out RNA-seq and SMAD1/5 ChIP-seq and employing a genome editing method, they show that the BMP-SMAD pathway is dispensable for maintaining naive pluripotency. Instead, the MEK5-ERK5 pathway mediates BMP-4-induced self-renewal of mESCs by inducing Klf2.


  • Identification of Drugs that Regulate Dermal Stem Cells and Enhance Skin Repair

    • Sibel Naska,
    • Scott A. Yuzwa,
    • Adam P.W. Johnston,
    • Smitha Paul,
    • Kristen M. Smith,
    • Maryline Paris,
    • Michael V. Sefton,
    • Alessandro Datti,
    • Freda D. Miller,
    • David R. Kaplan
    In this article, Kaplan, Miller, and colleagues performed screens to identify drugs already used in humans that enhance proliferation of skin-derived precursor (SKP) cells. They show that two of the compounds they identified, alprostadil and trimebutine maleate, promoted murine skin wound healing, likely by enhancing self-renewal of endogenous dermal precursors via activation of the MEK-ERK signaling pathway.
  • BMP-SMAD Signaling Regulates Lineage Priming, but Is Dispensable for Self-Renewal in Mouse Embryonic Stem Cells

    • Maria Gomes Fernandes,
    • Ruben Dries,
    • Matthias S. Roost,
    • Stefan Semrau,
    • Ana de Melo Bernardo,
    • Richard P. Davis,
    • Ramprasad Ramakrishnan,
    • Karoly Szuhai,
    • Elke Maas,
    • Lieve Umans,
    • Vanesa Abon Escalona,
    • Daniela Salvatori,
    • Dieter Deforce,
    • Wim Van Criekinge,
    • Danny Huylebroeck,
    • Christine Mummery,
    • An Zwijsen,
    • Susana M. Chuva de Sousa Lopes
    In this article, Chuva de Sousa Lopes and colleagues show that the BMP-SMAD signaling is dispensable for the derivation, maintenance, and self-renewal of mESCs both in “serum” and/or “2i” pluripotency states. The BMP-SMAD signaling plays a role regulating the levels of DNA methylation (via Dnmt3a/b and Tet1/2) and hence lineage priming in pluripotent mESCs.
  • CD13 and ROR2 Permit Isolation of Highly Enriched Cardiac Mesoderm from Differentiating Human Embryonic Stem Cells

    • Rhys J.P. Skelton,
    • Bevin Brady,
    • Suhail Khoja,
    • Debashis Sahoo,
    • James Engel,
    • Deevina Arasaratnam,
    • Kholoud K. Saleh,
    • Oscar J. Abilez,
    • Peng Zhao,
    • Edouard G. Stanley,
    • Andrew G. Elefanty,
    • Murray Kwon,
    • David A. Elliott,
    • Reza Ardehali
    CD13 and ROR2 mark pre-cardiac mesoderm precursors of definitive cardiac cell types. Ardehali and colleagues show that upon transplantation in a pig's heart, these cells engraft and differentiate to cardiomyocytes, endothelium, smooth muscle, and fibroblasts.
  • High-Content Analysis of CRISPR-Cas9 Gene-Edited Human Embryonic Stem Cells

    • Jared Carlson-Stevermer,
    • Madelyn Goedland,
    • Benjamin Steyer,
    • Arezoo Movaghar,
    • Meng Lou,
    • Lucille Kohlenberg,
    • Ryan Prestil,
    • Krishanu Saha
    Saha and colleagues show that a new culture and imaging platform, called ArrayEdit, allows both high-throughput and high-resolution subcellular imaging of thousands of hESC colonies in parallel. ArrayEdit generated CRISPR-Cas9-edited, living hESC lines at 82% efficiency within days. Biallelic edited cell lines at the LAMA5 locus did not contain any detectable off-target mutations and exhibited expected self-renewal defects upon subsequent characterization.
  • Identification of Distinct Breast Cancer Stem Cell Populations Based on Single-Cell Analyses of Functionally Enriched Stem and Progenitor Pools

    • Nina Akrap,
    • Daniel Andersson,
    • Eva Bom,
    • Pernilla Gregersson,
    • Anders Ståhlberg,
    • Göran Landberg
    By combining functional cancer stem cell enrichment strategies and single-cell gene expression analyses of key regulatory genes, Landberg, Ståhlberg, and colleagues identify distinct breast cancer stem cell clusters and hierarchical organization in breast cancer. Defining tumor cell states and their transitions allows for better identification and targeting of cancer stem cells.
  • Fetal Hematopoietic Stem Cell Transplantation Fails to Fully Regenerate the B-Lymphocyte Compartment

    • Eliver Eid Bou Ghosn,
    • Jeffrey Waters,
    • Megan Phillips,
    • Ryo Yamamoto,
    • Brian R. Long,
    • Yang Yang,
    • Rachel Gerstein,
    • Cheryl A. Stoddart,
    • Hiromitsu Nakauchi,
    • Leonore A. Herzenberg
    Ghosn and colleagues show that purified HSC transplantation selectively fails to regenerate B-1a, a subset of B cells known to be required for protection against pneumonia, influenza, and other infections. Moreover, HSC transplantation does not restore a key repertoire (VH11) of natural antibodies, raising the question of whether human HSC transplantation is sufficient to fully regenerate the immune system.
  • Long-Term In Vitro Expansion of Salivary Gland Stem Cells Driven by Wnt Signals

    • Martti Maimets,
    • Cecilia Rocchi,
    • Reinier Bron,
    • Sarah Pringle,
    • Jeroen Kuipers,
    • Ben N.G. Giepmans,
    • Robert G.J. Vries,
    • Hans Clevers,
    • Gerald de Haan,
    • Ronald van Os,
    • Robert P. Coppes
    Coppes and colleagues show that activation of Wnt signaling in EpCAMhigh cells purified from salivary gland (SG) tissue leads to the formation of organoids/miniglands, containing all SG lineages. Furthermore, Wnt proteins are required for self-renewal and robustly promote the long-term expansion of SG stem cells, which are efficiently able to regenerate radiation-damaged SG.