Methods comprising apoptosis inhibitors for the generation of transgenic pigs

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Stem Cell Related Patent Number US6613565

Title:Use of delta-like protein to inhibit the differentiation of stem cells
Inventors:Witte, Larry; Stormville, NY, USA
Pytowski, Bronislaw; New York, NY, USA
Moore, Kateri A.; Princeton, NJ, USA
Lemischka, Ihor R.; Princeton, NJ, USA
Summary:Described herein is a process of inhibiting stem cell differentiation by contact with a delta-like protein for maintaining and enriching stem cell populations. Primitive hematopoietic stem cells are described as being closely associated with discrete in vivo microenvironments, in which niches are thought to provide the molecular signals that mediate stem cell differentiation and self renewal. This invention relates to methods by which fetal liver microenvironment are dissected into distinct cellular components by establishing an extensive panel of stromal cell lines, one of which maintains repopulating stem cells for prolonged in vitro culture periods. Further disclosed is a subtraction cloning strategy which has yielded a cDNA encoding a cell surface glycoprotein with a restricted pattern of expression among stromal cell lines. This molecule, previously identified as dlk/Pref-1, is described as containing EGF-like repeats which are related to those in the Notch/Delta/Serrate family of proteins. Claims of the invention include the potential role of this molecule in hematopoietic stem and progenitor cell regulation. Also provided are means by which the dlk protein displays activity on purified stem cells by promoting the formation of cobblestone areas of proliferation, which contain both primitive high-proliferative potential progenitors as well as in vivo repopulating stem cells. Therapeutic applications are included, such as in replenishing hematopoietic stem cells in cancer patients undergoing chemotherapy.
Abstract:Primitive hematopoietic stem cells are closely associated with discrete in vivo microenvironments. These niches are thought to provide the molecular signals that mediate stem cell differentiation and self renewal. We have dissected the fetal liver microenvironment into distinct cellular components by establishing an extensive panel of stromal cell lines. One particular cell line maintains repopulating stem cells for prolonged in vitro culture periods. A subtraction cloning strategy has yielded a cDNA which encodes a cell surface glycoprotein with a restricted pattern of expression among stromal cell lines. This molecule, previously identified as dlk/Pref-1, contains EGF-like repeats which are related to those in the Notch/Delta/Serrate family of proteins. We have investigated the potential role of this molecule in hematopoietic stem/progenitor cell regulation. We show that the dlk protein displays activity on purified stem cells by promoting the formation of cobblestone areas of proliferation. These cobblestone areas contain both primitive high-proliferative potential progenitors as well as in vivo repopulating stem cells.
US Patent Website:Click Here for Full Text of Patent
Title Number:US6613565
Application Number:US1998000142027
Date Filed:08/12/1998
Date Published:02/09/2003
Assignee:ImClone Systems Incorporated, New York, NY, USA Trustees of Princeton University, Princeton, NJ, USA


 
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