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WO 2008/020815 Al (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 PCT 21 February 2008 (21.02.2008) WO 2008/020815 Al (51) International Patent Classification: (74) Agent: FOO, Moo Kwang; Axis Intellectual Captital Pte C12N 5/06 (2006.01) Ltd, 2 1A Duxton Road, Singapore 089487 (SG). (21) International Application Number: (81) Designated States (unless otherwise indicated, for every PCT/SG2007/000257 kind of national protection available): AE, AG, AL, AM, AT,AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ, CA, CH, (22) International Filing Date: 15 August 2007 (15.08.2007) CN, CO, CR, CU, CZ, DE, DK, DM, DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, IL, (25) Filing Language: English IN, IS, JP, KE, KG, KM, KN, KP, KR, KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, ME, MG, MK, MN, MW, (26) Publication Language: English MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PG, PH, PL, (30) Priority Data: PT, RO, RS, RU, SC, SD, SE, SG, SK, SL, SM, SV, SY, PCT/SG2006/000232 TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, 15 August 2006 (15.08.2006) SG ZM, ZW 60/878,222 3 January 2007 (03.0 1.2007) US (84) Designated States (unless otherwise indicated, for every (71) Applicant (for all designated States except US): kind of regional protection available): ARIPO (BW, GH, AGENCY FOR SCIENCE, TECHNOLOGY AND GM, KE, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, ZM, RESEARCH [SG/SG]; 20 Biopolis Way, #07-01 Centres, ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), Singapore 138668 (SG). European (AT,BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI, FR, GB, GR, HU, IE, IS, IT, LT,LU, LV,MC, MT, NL, PL, (72) Inventors; and PT, RO, SE, SI, SK, TR), OAPI (BF, BJ, CF, CG, CI, CM, (75) Inventors/Applicants (for US only): LIM, Sai Kiang GA, GN, GQ, GW, ML, MR, NE, SN, TD, TG). [SG/SG]; 60 Biopolis Street, Singapore 138672 (SG). LYE, Elias [SG/SG]; 60 Biopolis Street, Singapore Published: 138672 (SG). — with international search report (54) Title: MESENCHYMAL STEM CELL CONDITIONED MEDIUM (57) Abstract: We disclose a method of preparing a conditioned cell culture medium, the method comprising the steps of: (a) culturing a mesenchymal stem cell (MSC), a descendent thereof or a cell line derived therefrom in a cell culture medium; and (b) optionally isolating the cell culture medium; in which the mesenchymal stem cell (MSC) is obtained by propagating a cell obtained by dispersing a embryonic stem (ES) cell colony, or a descendent thereof, in the absence of co-culture in a serum free medium comprising FGF2. MESENCHYMAL STEM CELL CONDITIONED MEDIUM Reference is made to International Application PCT/SG2006/000232 filed August 15, 2006 and designating the US (applicant: Agency for Science, Technology and Research) in which inventor Lim is a co-inventor. Reference is also made to US provisional application serial no. US 60/878,222 filed January 3, 2007. The foregoing application, and each document cited or referenced in each of the present and foregoing applications, including during the prosecution of each of the foregoing application ("application and article cited documents"), and any manufacturer's instructions or catalogues for any products cited or mentioned in each of the foregoing application and articles and in any of the application and article cited documents, are hereby incorporated herein by reference. Furthermore, all documents cited in this text, and all documents cited or reference in documents cited in this text, and any manufacturer's instructions or catalogues for any products cited or mentioned in this text or in any document hereby incorporated into this text, are hereby incorporated herein by reference. Documents incorporated by reference into this text or any teachings therein may be used in the practice of this invention. Documents incorporated by reference into this text are not admitted to be prior art. FIELD The present invention relates to the fields of development, cell biology, molecular biology and genetics. More particularly, the invention relates to a method of deriving mesenchymal stem cells from embryonic stem cells. BACKGROUND Stem cells, unlike differentiated cells have the capacity to divide and either self- renew or differentiate into phenotypically and functionally different daughter cells (Keller, Genes Dev. 2005;19:l 129-1155; Wobus andBoheler, Physiol Rev. 2005;85:635-678; Wiles, Methods in Enzymology. 1993;225:900-918; Choi et al, Methods MoI Med. 2005;105:359-368). Mesenchymal stem cells (MSCs) are multipotent stem cells that have documented evidence of therapeutic efficacy in treating musculoskeletal injuries, improving cardiiac function in cardiovascular disease and ameliorating the severity of GVHD (Le Blanc and Pittenger, 2005). Being lineage restricted, they have limited but robust potential to differentiate into mesenchymal cell types, e.g adipocytes, chondrocytes and osteocytes, and have negligible risk of teratoma formation. Host immune rejection of transplanted MSCs is routinely circumvented through autologous or allogeneic transplantation. MSCs can be isolated from several adult tissues including bone marrow (BM), adipose tissues (ad), cord blood and expanded ex vivo. However, availability of tissues for their isolation remains limiting and requires risky invasive procedures, and ex vivo expansion of MSCs while significant, is nonetheless finite. The therapeutic capacity of MSCs to treat a wide spectrum of diseases in clinical and preclinical applications to treat a wide range of diseases [Al, A2] e.g. GVHD [Al] in musculoskeletal tissue bioengineering [A3,A4] and heart disease [A5,A6] has been attributed to their potential to differentiate into many different reparative cell types. However, the efficiency of transplanted MSCs to differentiate into functional reparative cells in the injured tissues or organs, and in therapeutically relevant numbers have never been adequately documented or demonstrated. This invention seeks to solve this and other problems with methods in the art. SUMMARY According to the invention, instead of using stem cells, injured or lost tissues may be regenerated or repaired through enhancement of endogenous tissue repair by applying secretions from MSCs instead of, or in addition to, MSCs themselves. Specifically, we provide for the use of conditioned media in which the MSCs derived from human embryonic stem cells are cultured in the treatment of disease.Thus, conditioned media may be used to treat any disease for which ES cells, specifically MSCs, are prescribed as being suitable for treating. We disclose the identity of polypeptides secreted by MSCs, and which form the components of the conditioned media. It will be evident that compositions comprising one or more specific biologically active compounds in the secretions of MSCs, in particular one or more of the 794 polypeptides, may be used instead of, or in addition to, the conditioned media in such treatment. With this approach, the present confounding issues associated with cell based therapy i.e. immune compatibility, tumorigenicity, xenozootic infections, costs, and waiting time if autologous cell preparations are used will be eliminated. Such an approach could potentially provide for the development of "off-the-shelf MSC-based therapeutics at affordable costs and with better quality control and consistency. The practice of the present invention will employ, unless otherwise indicated, conventional techniques of chemistry, molecular biology, microbiology, recombinant DNA and immunology, which are within the capabilities of a person of ordinary skill in the art. Such techniques are explained in the literature. See, for example, J. Sambrook, E. F. Fritsch, and T. Maniatis, 1989, Molecular Cloning: A Laboratory Manual, Second Edition, Books 1-3, Cold Spring Harbor Laboratory Press; Ausubel, F. M. et al. (1995 and periodic supplements; Current Protocols in Molecular Biology, ch. 9, 13, and 16, John Wiley & Sons, New York, N.Y.); B. Roe, J. Crabtree, and A. Kahn, 1996, DNA Isolation and Sequencing: Essential Techniques, John Wiley & Sons; J. M. Polak and James O'D. McGee, 1990, Oligonucleotide Synthesis: A Practical Approach, IrI Press; D. M. J. Lilley and J. E. Dahlberg, 1992, Methods ofEnzymology: DNA Structure Part A: Synthesis and Physical Analysis of DNA Methods in Enzymology, Academic Press; Using Antibodies : A Laboratory Manual : Portable Protocol NO. I by Edward Harlow, David Lane, Ed Harlow (1999, Cold Spring Harbor Laboratory Press, ISBN 0-87969-544-7); Antibodies : A Laboratory Manual by Ed Harlow (Editor), David Lane (Editor) (1988, Cold Spring Harbor Laboratory Press, ISBN 0-87969-314-2), 1855; and Lab Ref: A Handbook of Recipes, Reagents, and Other Reference Tools for Use at the Bench, Edited Jane Roskams and Linda Rodgers, 2002, Cold Spring Harbor Laboratoiy, ISBN 0-87969-630-3. Each of these general texts is herein incorporated by reference. BRIEF DESCRIPTION OF THE DRAWINGS Figures 1A-1G. Characterisation of hESC-MSC cultures. Figure IA. Cellular morphology under phase contrast. Figure IB. Expression of pluripotency-associated genes in hESC-MSC. Transcript levels are measured by Taqman-based quantitative RT-PCR and normalized to that of hESC. The transcript level in hESC is derived from the average of HuES9 and Hl liESC lines. Figure 1C. Western blot analysis for pluripotency-associated genes in HuES9 and H l hESC lines, HuES9.El HuES9.E3 and Hl. E2 hESC-MSC cultures and E14 mouse ESC line. _ Figure ID. Renal subcapsular transplantation of HuES9 and HuES9.El. Paraffin- embedded, H&E stained cross sections of kidney four months after transplantation with either HuES9.El (top) or HuES9 (bottom). Figure IE. Alkaline phosphatase activity in human HuES9 ESC line, mouse E14 ESC line, mouse embryonic fibroblast (MEF) feeder and HuES9.El. Figure IF. Genomic DNA analysis by PCR for the presence of human AIu and mouse c-mos repeat sequences.
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