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(12) Patent Application Publication (10) Pub. No.: US 2015/0050728A1 Benvenisty Et Al

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(12) Patent Application Publication (10) Pub. No.: US 2015/0050728A1 Benvenisty Et Al US 2015.0050728A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2015/0050728A1 Benvenisty et al. (43) Pub. Date: Feb. 19, 2015 (54) IDENTIFICATION OF NOVEL CELL (60) Provisional application No. 61/536,099, filed on Sep. SURFACE MARKERS FOR PANCREATC 19, 2011, provisional application No. 61/417.364, PROGENITOR CELLS AND DEFINITE filed on Nov. 26, 2010. ENDODERMAL CELLS Publication Classification (71) Applicants: Nissim Benvenisty, Jerusalem (IL); Joseph Itskovitz-Eldor, Haifa (IL); (51) Int. Cl. Bettina Fishman, Haifa (IL); Hanna CI2N5/071 (2006.01) Segev, Doar-Na Emek Hefer (IL); (52) U.S. Cl. Danny Kitsberg, Jerusalem (IL) CPC .................................... CI2N5/0678 (2013.01) USPC .......................................................... 435/325 (72) Inventors: Nissim Benvenisty, Jerusalem (IL); Joseph Itskovitz-Eldor, Haifa (IL); (57) ABSTRACT Bettina Fishman, Haifa (IL); Hanna Segev, Doar-Na Emek Hefer (IL); Methods of identifying, isolating and qualifying pancreatic Danny Kitsberg, Jerusalem (IL) progenitor cells and definite endodermal cells. An isolated population of pancreatic progenitor cells, including at least (21) Appl. No.: 14/528,837 75% of cells having a TROP-2+ and/or TROP-2+/GPR50+ expression pattern and an isolated population of definite (22) Filed: Oct. 30, 2014 endodermal cells, including at least 50% of cells having a SOX17+/SOX7+/GSC+/CER+/FOXA2+/CXCR4+f Related U.S. Application Data NANOG expression pattern. Nucleic acid constructs includ (63) Continuation of application No. 13/903,815, filed on ing a reporter protein under the transcriptional regulation of May 28, 2013, which is a continuation of application SOX17 regulatory sequence or of PDX1 regulatory sequence, No. PCT/IB2011/055283, filed on Nov. 24, 2011. and cells comprising same, and methods and kits using same. Patent Application Publication Feb. 19, 2015 Sheet 1 of 20 US 2015/0050728A1 Olz88gy,1989 09099 Patent Application Publication Feb. 19, 2015 Sheet 2 of 20 US 2015/0050728A1 : Patent Application Publication Feb. 19, 2015 Sheet 3 of 20 US 2015/0050728A1 O re 103 is104 FIG. 2F FIG. 2B FIG. 2C FG. 2D FIG. 2E FG. 2G Patent Application Publication Feb. 19, 2015 Sheet 4 of 20 US 2015/0050728A1 : DXOS O) eNeel+). LXOSuluOSSeldx Patent Application Publication Feb. 19, 2015 Sheet 5 of 20 US 2015/0050728A1 Patent Application Publication Feb. 19, 2015 Sheet 6 of 20 US 2015/0050728A1 9/ZZZ 999||Z. 0/0/| (O9 C19 0996 0/| 0/| Patent Application Publication Feb. 19, 2015 Sheet 7 of 20 US 2015/0050728A1 s s Patent Application Publication Feb. 19, 2015 Sheet 8 of 20 US 2015/0050728A1 i s O a. o X liT a 8 2 N 2 LL t CD d O d - - P L S 2 C Se (60) S9 pel-OSun O) eNeel uOSSeldx. Patent Application Publication Feb. 19, 2015 Sheet 10 of 20 US 2015/0050728A1 Newly identified markers 3 : cric 2.5 sext 15 FIG. 5B only o: TMEM45A, RELL2, O ... PPFA4 -0,5 . - -15 -2. i PDX1 only 33 F.G. 5C SILV, GPR50 2 --- 8-2 S-3 4 -5). SOX7 and aE 23 - mo, W. W. PDX1 , | STX16, DLK1, FIG. 5D So CPTC, LRP2, is BST2 Y -2 -3 F.G. 5E PDX1 and , TROP-2 pancreas O 3. -4 m-m-m- ES SOX17 POX Pancreas Patent Application Publication Feb. 19, 2015 Sheet 11 of 20 US 2015/0050728A1 ( e8. UOISS80X 20|| 0. 0- 0. WOI-AdS) Patent Application Publication Feb. 19, 2015 Sheet 12 of 20 US 2015/0050728A1 4990’0- ene/\ueeW WWWW Patent Application Publication Feb. 19, 2015 Sheet 13 of 20 US 2015/0050728A1 -0009 |0098 |0008 |009, |000Z '00s,|0001 -009 uOSSeldx. Patent Application Publication Feb. 19, 2015 Sheet 14 of 20 US 2015/0050728A1 SeÐJOuedun Patent Application Publication Feb. 19, 2015 Sheet 15 of 20 US 2015/0050728A1 ********* |-0 |000) |-0009 uOSSeld){ /|XOS, ?XOld: S29JOU20-) Patent Application Publication Feb. 19, 2015 Sheet 16 of 20 US 2015/0050728A1 . s rawaiigwakizolcocercoaxwortargowice C O O O O O O O O O O O CC d N CY) CN r uOSSeudy N C St M) : x 8 Patent Application Publication Feb. 19, 2015 Sheet 17 of 20 US 2015/0050728A1 New Endodermal surface markerS F.G. 12A EBSD7 FIG. 12D EBSD7 X. ES53.ES-2.25% 150 a , ES-1.34%ESS3.3% 150- o 3 3 ; ,100 2100 2 50 - 50 O FIG. 12E 150 150 A EBS-16.13%ES2.28% to 100 ES:53,EBS-1.71% it s o,- . 3 £ I 50 F.G. 12C ES-0.26% | A en s Patent Application Publication Feb. 19, 2015 Sheet 18 of 20 US 2015/0050728A1 BST2 and KDR in DE treated Cells F.G. 13A FIG. 13B 2-IDE-KDR Patent Application Publication Feb. 19, 2015 Sheet 19 of 20 US 2015/0050728A1 CXCR4 (+) KDR(-) IDE treated cells 10' CXCR4(+)KDR (-) - L3-00Sitivet FIG. 13D Patent Application Publication Feb. 19, 2015 Sheet 20 of 20 US 2015/0050728A1 FIG. 14A F.G. 14B FIG. 14C US 2015/0050728A1 Feb. 19, 2015 IDENTIFICATION OF NOVEL CELL endoderm and PDX1 is expressed at onset of the earliest SURFACE MARKERS FOR PANCREATC commitment stages towards pancreas (12). PROGENITOR CELLS AND DEFINITE 0006 Lavonet al. (25) transfected hESCs with a reporter ENDODERMAL CELLS construct which included the enhanced green fluorescent pro tein (EGFP) under the albumin promoter (ALB-eGFP). FIELD OF THE INVENTION 0007 Additional background art includes Wang P. et al. Cell StemCell, 8:335-346, 2011; WO 2005116073; Zwaka T 0001. The present invention, in some embodiments P and J A Thomson, 2003 Homologous recombination in thereof, relates to methods of identifying, isolating and quali human embryonic stem cells. Nat Biotechnol 21:319-321: fying pancreatic progenitor cells and definite endodermal Micallef S.J., 2005 (Diabetes 54; 301-305); Nikakan K.K., cells, and, more particularly, but not exclusively, to isolated 2010 (Genes Dev. 24:312-326); D'Amour KA, et al., 2005 cell populations generated thereby. (Efficient differentiation of human embryonic stem cells to definitive endoderm. Nat Biotechnol 23:1534-1541); Yasu BACKGROUND OF THE INVENTION naga M, et al., 2005 (Induction and monitoring of definitive and visceral endoderm differentiation of mouse ES cells. Nat 0002 Type 1 Diabetes Mellitus is an autoimmune disease Biotechnol 23:1542-1550); US 2011/0070645 (Chen et al.); affecting the life of millions worldwide with enormous finan WO 2005/116073 A2 (D'Amour KA et al.); Borowiak M, cial costs. It is caused by the destruction and loss of function 2009 (Cell Stem Cell 4, 348-358); Jiang W., 2007 (Cell Res of beta cells in the pancreatic Islets of Langerhans. The lack of 17:333-344); D'amour 2006 (Nat Biotechnol 24:1392-1401): insulin production causes deregulation of blood glucose lev and Kroon 2008 (Nat Biotechnol 26:443-452). els, and leads to a large number of symptoms that can even tually be fatal. Daily insulin injections are the most prevalent SUMMARY OF THE INVENTION treatment for type I Diabetes Mellitus and for insulin-depen dent type II Diabetes Mellitus. However, insulin injections 0008 According to an aspect of some embodiments of the are expensive, cumbersome and do not enable the patient to present invention there is provided a method of identifying attain a real steady state in blood glucose levels, but instead pancreatic progenitor cells, comprising determining in a lead to fluctuations above and below the optimal base line, population of cells which comprises pancreatic progenitor which do not ultimately prevent complications of diabetes. A cells at least one marker that is: (i) positively associated with potential cure for these diseases is transplantation therapy pancreatic differentiation, the marker being selected from the whereby islets are transplanted into the patient. However, the group consisting of TACSTD2 (TROP-2), GPR50, BST2, limited number of donor organs presently restricts the use of NTRK2, ITGA4, KDR, PTPRN, LGI1, VIPR2, SLC2A1, this procedure. MUC15, MUC12, LPHN3, MUC16, VTCN1, MMP16, 0003 New sources of beta cells are needed in order to FZD3, ITGB6, GFRA3, ROBO1, NLGN1, BST2, MUC12, develop cell therapies for patients with insulin-dependent CNTFR, LPHN1, SULF1, ADAM23, SCUBE3, PLAU, diabetes. An alternative to forced expansion of post-mitotic CDON, SLIT2, C7orf68, PLXDC2, CD74, MUC15, GPR56, beta cells is the induction of differentiation of pluripotent VTCN1, ITGB6, NTRK2, AREG, BOC, ITGA4, KLRK1, stem/progenitor cells (which have a natural self-expansion PRTG, PTPRZ1, GABRP, SILV, KIAA 1772, PLP1, OVOS, capacity) of different origins, into insulin-producing cells. HAPLN1, EPHA7, ENO2, PCDHB5, OVOS, SYT1, DCT, Various publications describe protocols for differentiation of GPAM, SLITRK6, DCC, FREM2, SDK2, CGA, ATP1B2, human embryonic stem cells (hESCs) (5-9), induced pluri SEMA3D, PCDHB15, CDH1, WNT8B, LPAR4, NPIPL3, potent stem cells (iPSCs) (10, 11), or cord blood mesenchy FAM171B, PTN, ABCC2, ADAMTS3, RASA4, CPT1C, mal stem cells (Chao C K et al., PLoS ONE. 2008; 3(1): SLC6A6, PCDHB3, LRRC37B, RNFT2, KCNG3, TRPC1, e1451; Santos T M et al., Transplantation Proceedings, 42: ALPPL2, OR4F21, CCL2, KIF5A, OLFM2, CACNG7, 563-565, 2010; Bhandari DRet al., Differentiation. 2011 Jul. MPHOSPH9, SLC13A4, MOXD1, C6orf186, SLC4A8, 20. Epub ahead of print) into pancreatic endocrine cells STX16, AMY2A, SPARCL1, MGP A2M, DCN, ATP8B1, which might provide a source of insulin producing cells for MMRN1, EMP1, PLA2G2A, PDE3A, TLR3, CYP1B1, diabetics. PTGIS, RFTN2, PLEKHA2, SMOC1, STOM, JAM2, CHL1, SCG5, IGFBP7, NPR3, IFI6, CR1L, OR2A4, OR2A7, 0004. The in vitro differentiation of cells to pancreatic beta KCNG3, CACNG7, GRID2, CDH1, LPAR3, SEMA6A, cells, like in vivo embryonic development, is a stepwise pro PTPRZ1 ATP1A3, CAMKV, SCNN1G, SYT6, SLC18A2, cess by which the initially pluripotent/multipotent cells, such PCDHB5, ABCG2, HLA-DRA, CR1L, HTR2C, EDNRB, as human ESCs or iPSCs, progressively commit towards a PCDH11X, SLC17A7, SCNN1A, CD9, CXCL16, FXYD5, more specialized cell fate ultimately resulting in insulin pro GABRO, GFRA3, CACNA2D2, CLDN4, PTPRN, PLP1, ducing cells.
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