Signaling Chemicals Stimulate Stem Cell Growth; May Boost Ex Vivo Growth

[Guest guest]

[There has been the tantalizing idea of boosting stem cell growth

outside the body for use in stem cell transplants and other uses;

this abstract is along these same lines.

This may come into play in cord-blood transplantation, since the

advantages of cord blood is largely offset by their very small

numbers. Boosting the number of stem cells from umbilical cords may

on day lead to a greater use of this infrequent procedure.]

Blood First Edition Paper, prepublished online May 25, 2004

Submitted March 4, 2004

Accepted May 10, 2004

Extracellular nucleotides are potent stimulators of human

hematopoietic stem cells in vitro and in vivo

o M Lemoli*, e Ferrari, Miriam Fogli, Lara Rossi, Cinzia

Pizzirani, Sylvia Forchap, Paola Chiozzi, Diletta Vaselli, Francesco

Bertolini, Foutz, Michela Aluigi, Michele Baccarani, and

Francesco Di Virgilio

Institute of Hematology and Medical Oncology, 'L. & A. Seragnoli',

University of Bologna, Bologna, Italy

Department of Experimental and Diagnostic Medicine, Section of

General Pathology, University of Ferrara, Ferrara, Italy

Department of Hematology, European Institute of Oncology, Milan, Italy

Although extracellular nucleotides support a wide range of biological

responses of mature blood cells, little is known on their effect on

blood cell progenitor cells.

In this study, we assessed whether receptors for extracellular

nucleotides (P2 receptors, P2R) are expressed on human hematopoietic

stem cells (HSC), and whether activation by their natural ligands,

ATP and UTP, induces HSC proliferation in vitro and in vivo. Our

results demonstrated that CD34+ HSC express functional P2XR and P2YR

of several subtypes. Furthermore, stimulation of CD34+ cells with

extracellular nucleotides caused a fast release of Ca2+ from

intracellular stores and an increase in ion fluxes across the plasma

membrane.

Functionally, ATP and, to a higher extent, UTP acted as potent early-

acting growth factors for HSC, in vitro, as they strongly enhanced

the stimulatory activity of several cytokines on clonogenic CD34+ and

lineage negative CD34- progenitors and expanded more primitive CD34+-

derived long-term culture-initiating cells. Furthermore, xenogenic

transplant studies showed that short-term pre-incubation with UTP

significantly expanded the number of marrow repopulating HSC in

nonobese diabetic/severe combined immunedeficiency mice.

Our data suggest that extracellular nucleotides may provide a novel

and powerful tool to modulate HSC functions.