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Icahn School of Medicine at Mount Sinai

Kateri Moore

Ihor R Lemischka

Bronislaw Pytowski

Larry Witte

Carlos Filipe Pereira

The disclosure relates to the development of methods for making hematopoietic stem cells from differentiated cells by introducing and expressing transcription factors. More particularly, the disclosure provides methods for redirecting differentiated cells to a hematopoietic stem cell state or to a hemogenic endothelial cell state by direct programming with specific combinations of transcription factors.

Methods for programming differentiated cells into hematopoietic stem cells

Primitive hematopoietic stem cells are closely associated with discrete in vivo microenvironments. These &ldquo;niches&rdquo; 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 &ldquo;cobblestone areas&rdquo; of proliferation. These cobblestone areas contain both primitive high-proliferative potential progenitors as well as in vivo repopulating stem cells.

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Princeton, NJ, United States of America

Kateri Moore