Cyclic ADP-ribose generation by CD38 improves human hemopoietic stem cell engraftment into NOD/SCID mice.
Cyclic ADP-ribose (cADPR) is a potent and universal intracellular calcium mobilizer, recently shown to behave as a new hemopoietic cytokine stimulating the in vitro proliferation of both committed and uncommitted human hemopoietic progenitors (HP). Here, we investigated the effects of cADPR on engraftment of hemopoietic stem cells (HSC) into irradiated NOD/SCID mice. Two different protocols were used: i) a 24 h in vitro priming of cord blood-derived mononuclear cells (MNC) with micromolar cADPR, followed by their infusion into irradiated mice (both primary and secondary transplants); and ii) co-infusion of MNC with CD38-transfected, cADPR-generating, irradiated murine 3T3 fibroblasts. We demonstrated a dual effect of cADPR on human HP in vivo: i) enhanced proliferation of committed progenitors, responsible for improvement of short-term engraftment; ii) expansion of HSC, with increased long-term human engraftment into secondary recipients and a significantly higher expansion factor of CD34+ progenitors in mice co-infused with MNC and CD38+ 3T3 fibroblasts. These results hold promise for the possible therapeutic use of cADPR, and of cADPR-producing stroma, to achieve long-term expansion of human HSC, that is, those HP capable of self-renewal and responsible for repopulation of the bone marrow.
Podestà
Marina
M
Department of Hematology, 2nd Division, S. Martino Hospital, Genoa, Italy. marina.podesta@hsanmartino.liguria.it
Pitto
Anna
A
Figari
Osvaldo
O
Bacigalupo
Andrea
A
Bruzzone
Santina
S
Guida
Lucrezia
L
Franco
Luisa
L
De Flora
Antonio
A
Zocchi
Elena
E
D016475:3T3 Cells; D036541:ADP-ribosyl Cyclase / Q000235:genetics / Q000502:physiology*; D051997:ADP-ribosyl Cyclase 1; D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D018952:Antigens, CD34 / Q000276:immunology; D015214:Antigens, Differentiation, Myelomonocytic / Q000276:immunology; D036563:Cyclic ADP-Ribose / Q000096:biosynthesis* / Q000494:pharmacology; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007958:Leukocyte Count; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000276:immunology; D008562:Membrane Glycoproteins; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D063268:Sialic Acid Binding Ig-like Lectin 3; D014183:Transplantation, Heterologous
D015703:Antigens, CD; D018952:Antigens, CD34; D015214:Antigens, Differentiation, Myelomonocytic; C571163:CD33 protein, human; C571165:Cd33 protein, mouse; D008562:Membrane Glycoproteins; D063268:Sialic Acid Binding Ig-like Lectin 3; D036563:Cyclic ADP-Ribose; D036541:ADP-ribosyl Cyclase; C498154:CD38 protein, human; C498155:Cd38 protein, mouse; D051997:ADP-ribosyl Cyclase 1