Use of delta-like protein to inhibit the differentiation of stem cells

US6613565B1 · kind B1 · utility

Assignees

• ImClone Systems Incorporated · US
• THE TRUSTEES OF PRINCETON UNIVERSITY · US

Inventors

• Larry Witte · Stormville, US
• Bronislaw Pytowski · New York, US
• Kateri Moore · Princeton, US
• Ihor R. Lemischka · Princeton, US

Key dates

• Filing date: Dec 8, 1998
• Grant date: Sep 2, 2003
• Expiry date: Dec 8, 2018

Classification

• Technology area (CPC C): Chemistry; Metallurgy
• CPC primary: C12N2502/99
• WIPO field: Biotechnology
• WIPO sector: Chemistry

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.