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(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date _ . ... , . _ . 5 May 2011 (05.05.2011) WO 2011/050470 Al (51) International Patent Classification: Master University, 1200 Main Street West, MDCL 5029, C12N 5/071 (2010.01) C12Q 1/02 (2006.01) Hamilton, Ontario L8N 3Z5 (CA). RAMPALLI-DESH- A61K 35/12 (2006.01) C12Q 1/68 (2006.01) PANDE, Shravanti [IN/CA]; Stem Cell and Cancer Re C12N 15/00 (2006.01) C12N 15/867 (2006.01) search Institute, McMaster University, 1200 Main Street West, MDCL5029, Hamilton, Ontario L8N 3Z5 (CA). (21) International Application Number: MUNOZ RISUENO, Ruth [ES/CA]; Stem Cell and PCT/CA20 10/00 1708 Cancer Research Institute, McMaster University, 1200 (22) International Filing Date: Main Street West, MDCL5029, Hamilton, Ontario L8N 29 October 2010 (29.10.2010) 3Z5 (CA). VIJAYARAGAVAN, Kausalia [CA/ES]; Stem Cell and Cancer Research Institute, McMaster Uni (25) Filing Language: English versity, 1200 Main Street West, MDCL5029, Hamilton, (26) Publication Language: English Ontario L8N 3Z5 (CA). (30) Priority Data: (74) Agent: BERESKIN & PARR LLP/S.E.N.C.R.L., 61/256,1 70 29 October 2009 (29.10.2009) US S.R.L.; 40 King Street West, 40th Floor, Toronto, On tario M5H 3Y2 (CA). (71) Applicant (for all designated States except US): MC¬ MASTER UNIVERSITY [CA/CA]; McMaster Industry (81) Designated States (unless otherwise indicated, for every Liaison Office (MILO), McMaster Innovation Park, 175 kind of national protection available): AE, AG, AL, AM, Longwood Road South, Room 305, Hamilton, Ontario AO, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ, L8P 0A1 (CA). CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, (72) Inventors; and HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, (75) Inventors/ Applicants (for US only): BHATIA, Mickie KR, KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, [CA/CA]; Stem Cell and Cancer Research Institute, Mc ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, Master University, 1200 Main Street West, MDCL5029, NO, NZ, OM, PE, PG, PH, PL, PT, RO, RS, RU, SC, SD, Hamilton, Ontario L8N 3Z5 (CA). SZABO, Eva SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR, [CA/CA]; Stem Cell and Cancer Research Institute, Mc TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. [Continued on next page] (54) Title: GENERATING INDUCED PLURIPOTENT STEM CELLS AND PROGENITOR CELLS FROM FIBROBLASTS (57) Abstract: The present disclosure provides a method of generating progenitor cells, such as hematopoietic or neural progenitor cells, from fibroblasts, such as dermal fibroblasts, compris ing providing fibroblasts that express or are treated with a POU domain containing gene or protein and culturing the cells under conditions that allow production of progenitor cells, with out traversing the pluripotent state. Also pro vided is a method of isolating a subpopulation of fibroblasts with reprogramming potential comprising providing fibroblasts that express an Oct-4-reporter and isolating cells that are positive for the reporter. Further provided is a method of generating reprogrammed fibroblast- derived induced pluripotent stem cells. Also provided are uses and assays of the cells pro duced by the methods of the disclosure. w o 2011/050470 Ai II II II I III I1 1 llll II II II II III II I II (84) Designated States (unless otherwise indicated, for every — of inventorship (Rule 4.1 7(iv)) kind of regional protection available): ARIPO (BW, GH, GM, KE, LR, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, Published: ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, — with international search report (Art. 21(3)) TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, — before the expiration of the time limit for amending the LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, claims and to be republished in the event of receipt of SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, amendments (Rule 48.2(h)) GW, ML, MR, NE, SN, TD, TG). — with sequence listing part of description (Rule 5.2(a)) Declarations under Rule 4.17: — as to applicant's entitlement to apply for and be granted a patent (Rule 4.1 7(H)) Title: GENERATING INDUCED PLURIPOTENT STEM CELLS AND PROGENITOR CELLS FROM FIBROBLASTS Cross Reference to Related Applications [0001] This application claims the benefit of priority of copending U.S. provisional application 61/256,170 filed on October 29, 2009, the contents of which are incorporated herein by reference in their entirety. Field of the disclosure [0002] The disclosure relates to reprogramming of fibroblasts. In particular, the disclosure relates to methods of generating progenitor cells and induced pluripotent stems cells derived from fibroblasts and the cells produced by the methods. Background of the disclosure [0003] Several groups have demonstrated the ability to reprogram human fibroblasts to induced pluripotent stem cells (iPSCs) following transduction with Oct-4 together with other factors (Takahashi et al., 2007; Takahashi and Yamanaka, 2006; Yu et al., 2007). For example, dermal fibroblasts can be reprogrammed to a pluripotent state by ectopic expression of a cocktail of pluripotent factors including Oct-4 (POU5F1), Sox-2, Klf-4, c- Myc, Nanog, and Lin28 (Takahashi et al., 2007; Yu et al., 2007), With the exception of Oct4, further studies indicated that the majority of these factors could be eliminated by use of unique stem/progenitor cells (Heng et al.; Aasen et al. 2008; Eminli et al. 2008; Eminli et al. 2009; Kim et al. 2009) or, alternatively, by addition of chemicals targeting the epigenome of dermal fibroblast sources (Shi et al. 2008; Lyssiotis et al. 2009). These studies demonstrate there are several approaches and methods for generation of iPSCs, however, the cellular and molecular mechanisms underlying reprogramming to the pluripotent state remain largely unknown (Jaenisch and Young, 2008). Although iPSCs can be differentiated towards the blood fate, the resulting hematopoietic cells preferentially generate primitive blood cells that utilize embryonic programs. Moreover, the methods remain inefficient, making it difficult to contemplate transplantation or modeling hematological diseases (Lengerke and Daley, 2010). Characterization of these processes is further complicated by cellular intermediates that fail to establish a stable piuripotent state, potentially due to the inability to achieve the correct combination, stoichiometry, or expression levels of reprogramming factors ideal for complete pluripotency induction (Chan et al., 2009; Kanawaty and Henderson, 2009; Lin et al., 2009; Mikkelsen et al., 2008). Consistent with this idea, intermediate cells derived from fibroblasts have been shown to co- express genes associated with several differentiated lineages (neurons, epidermis, and mesoderm) (Kanawaty and Henderson, 2009; Mikkelsen et al., 2008), nevertheless the exact identity and differentiation potential of these cell types remain elusive. This creates the possibility that under unique conditions the fibroblasts expressing a small subset of transcription factors can be induced to differentiate towards specified lineages without achieving pluripotency, as recently been demonstrated by converting fibroblasts into specific cell types such as neurons, cardiomyocytes, and macrophage-like cells (Feng et al., 2008; leda et al., 2010; Vierbuchen et al., 2010). While these studies have examined fibroblast conversion in the murine model, this concept remains to be extrapolated for human applications. [0004] Previous studies have shown that proteins containing POU domains, such as Oct-4, along with Oct-2 (POU2F2) and Oct- (POU2F1) bind similar DNA target motifs (Kang et al., 2009). Whilst both Oct-2 and Oct- 1 play a role in hematopoietic development (Brunner et al., 2003; Emslie et al., 2008; Pfisterer et al., 1996), Oct-4 is yet to be implicated in this process. Nonetheless, recent studies have predicted that Oct-4 possesses the capacity to bind to the promoters of the hematopoietic genes Runxl and CD45, thus potentially regulating their expression (Kwon et al., 2006; Sridharan et al., 2009). Despite the similarities in binding and regulation, the exact functional role of individual Oct family members appears to be cell context specific (Kang et al., 2009; Pardo et al., 2010). [0005] The ability to generate piuripotent stem cells from human dermal fibroblasts allows for generation of complex genetic disease models, and provides an unprecedented source for autologous transplantation without concern of immune rejection (Takahashi and Yamanaka 2006; Hanna et al. 2007; Yu et al. 2007; Okita et al. 2008; Park et al. 2008; Park et al. 2008b; Soldner et al. 2009). [0006] Although a variety of somatic cell types can be reprogrammed, the vast majority of studies aimed at characterizing the mechanisms that govern the reprogramming process utilize fibroblasts (Takahashi and Yamanaka 2006; Takahashi et al. 2007; Wernig et al. 2007; Yu et al. 2007; Aoi et al. 2008; Brambrink et al. 2008; Eminli et al. 2008; Hanna et al. 2008; Huangfu et al. 2008; Lowry et al. 2008; Stadtfeld et al. 2008; Zhou et al. 2008; Carey et al. 2009; Feng et al. 2009; Gonzalez et al. 2009; Guo et al. 2009; Kaji et al. 2009; Utikal et al. 2009; Woltjen et al. 2009; Yusa et al. 2009; Zhou et al. 2009). As such, the current understanding of the molecular mechanisms and cellular nature of reprogramming is nearly exclusively derived from fibroblast-based reprogramming. Fibroblasts can be generated from multiple tissue sites including dermal skin, however, little is known about the origins and composition of fibroblasts used experimentally. [0007] Cellular reprogramming to the pluripotent state was originally demonstrated using in vitro cultured mammalian fibroblasts (Takahashi and Yamanaka 2006).
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  • T Cell Depending on the Differentiation State of the Dual

    T Cell Depending on the Differentiation State of the Dual

    Dual Effects of Sprouty1 on TCR Signaling Depending on the Differentiation State of the T Cell This information is current as Heonsik Choi, Sung-Yup Cho, Ronald H. Schwartz and of September 29, 2021. Kyungho Choi J Immunol 2006; 176:6034-6045; ; doi: 10.4049/jimmunol.176.10.6034 http://www.jimmunol.org/content/176/10/6034 Downloaded from References This article cites 63 articles, 29 of which you can access for free at: http://www.jimmunol.org/content/176/10/6034.full#ref-list-1 http://www.jimmunol.org/ Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication by guest on September 29, 2021 *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2006 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Dual Effects of Sprouty1 on TCR Signaling Depending on the Differentiation State of the T Cell1 Heonsik Choi,* Sung-Yup Cho,† Ronald H. Schwartz,* and Kyungho Choi2* Sprouty (Spry) is known to be a negative feedback inhibitor of growth factor receptor signaling through inhibition of the Ras/ MAPK pathway.
  • Transcriptomic and Epigenomic Characterization of the Developing Bat Wing

    Transcriptomic and Epigenomic Characterization of the Developing Bat Wing

    ARTICLES OPEN Transcriptomic and epigenomic characterization of the developing bat wing Walter L Eckalbar1,2,9, Stephen A Schlebusch3,9, Mandy K Mason3, Zoe Gill3, Ash V Parker3, Betty M Booker1,2, Sierra Nishizaki1,2, Christiane Muswamba-Nday3, Elizabeth Terhune4,5, Kimberly A Nevonen4, Nadja Makki1,2, Tara Friedrich2,6, Julia E VanderMeer1,2, Katherine S Pollard2,6,7, Lucia Carbone4,8, Jeff D Wall2,7, Nicola Illing3 & Nadav Ahituv1,2 Bats are the only mammals capable of powered flight, but little is known about the genetic determinants that shape their wings. Here we generated a genome for Miniopterus natalensis and performed RNA-seq and ChIP-seq (H3K27ac and H3K27me3) analyses on its developing forelimb and hindlimb autopods at sequential embryonic stages to decipher the molecular events that underlie bat wing development. Over 7,000 genes and several long noncoding RNAs, including Tbx5-as1 and Hottip, were differentially expressed between forelimb and hindlimb, and across different stages. ChIP-seq analysis identified thousands of regions that are differentially modified in forelimb and hindlimb. Comparative genomics found 2,796 bat-accelerated regions within H3K27ac peaks, several of which cluster near limb-associated genes. Pathway analyses highlighted multiple ribosomal proteins and known limb patterning signaling pathways as differentially regulated and implicated increased forelimb mesenchymal condensation in differential growth. In combination, our work outlines multiple genetic components that likely contribute to bat wing formation, providing insights into this morphological innovation. The order Chiroptera, commonly known as bats, is the only group of To characterize the genetic differences that underlie divergence in mammals to have evolved the capability of flight.