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Effect of nicotine on fetal hemopoietic stem cell migration

Institution: La Jolla Institute for Molecular Medicine
Investigator(s): Sophia Khaldoyanidi, M.D., Ph.D.
Award Cycle: 2002 (Cycle 11) Grant #: 11IT-0020 Award: $152,352
Subject Area: Cardiovascular Disease
Award Type: Inno Dev & Exp Awards (IDEAS)

Initial Award Abstract
Studies of the effects of cigarette smoking by pregnant women on intrauterine development of the offspring are foremost, since the development of the child is likely to be hindered. Infants whose mothers smoked during pregnancy have lower size and weight at birth and are not only predisposed to pulmonary and cardiovascular diseases, but also to a severe immunodeficiency. Thus, the goal of this grant application is to understand the cellular and molecular mechanisms leading to dysfunction of the immune system in children whose mothers smoked during pregnancy.

Hematopoiesis, generation of mature blood cells, is vital for life: the white cells fight infections, the red cells carry oxygen throughout the body, and the platelets promote healing and prevent bleeding. The hematopoietic stem cell is a progenitor cell that generates all varieties of mature blood cells throughout life. During adult life, hematopoiesis takes place in the bone marrow. However, colonization of the bone marrow with primitive hematopoietic stem cells must occur during intrauterine development of the fetus. Thus, any changes in the ability of primitive hematopoietic stem cells to egress from the fetal liver, to immigrate into the fetal bone marrow and to establish normal hematopoiesis could be deleterious to the newborn. Nicotine is one such factor, the exposure to which could lead to serious alterations in the bone marrow development, resulting in a disruption of hematopoietic homeostasis and a changed ratio of mature cells in the blood. Indeed, we have demonstrated that newborn mice exposed to nicotine during intrauterine development have a lower number of hematopoietic stem cells in the bone marrow in comparison to control animals. Furthermore, these mice had severe immunodeficiency during the first month after birth. Based on our preliminary observations, we propose to investigate how nicotine can alter the ability of bone marrow stromal cells to produce soluble factors that mediate migration of hematopoietic stem cells, colonization of the bone marrow and production of mature blood cells. In addition, we plan to examine whether nicotine-induced immunodeficiency in newborn mice is due to inhibition of the functional activity of the immune cells or is a result of impaired colonization of the bone marrow with hematopoietic stem cells and lower production of lymphoid progenitor cells and, consequently, mature immune cells.

The proposed grant application will use the current knowledge in experimental hematology to understand the cellular and molecular mechanisms that affect embryonic development of the hematopoietic and immune systems. Studying the effect of nicotine on intrauterine development may open a new area of research, which could ultimately establish a basis for novel therapeutic approaches to the treatment of tobacco-related immunodeficiency.

Exposure to nicotine during gestation affects trafficking of fetal hematopoietic stem cells.
Periodical: American Society of Hematology Index Medicus:
Authors: Khaldoyanidi S, Orlovskaya I ABS
Yr: 2002 Vol: 100 Nbr: 16 Abs: 4235 Pg: 184b