Effects of nicotine on fetal hematopoiesis

Institution:	Torrey Pines Institute for Molecular Studies
Investigator(s):	Sophia Khaldoyanidi, M.D., Ph.D.
Award Cycle:	2007 (Cycle 16)	Grant #: 16RT-0134	Award: $764,400
Subject Area:	General Biomedical Science
Award Type:	Research Project Awards

Abstracts

Initial Award Abstract

Studies of the effects of cigarette smoking by pregnant women on the intrauterine development of their offspring are most important, since the development of the child is likely to be hindered. Infants whose mothers smoked during pregnancy are of lower size and weight at birth and are not only predisposed to pulmonary and cardiovascular diseases, but also to immunodeficiency. Thus, the goal of this grant application is to understand the cellular and molecular mechanisms leading to the dysfunction of the immune system in children whose mothers smoked during pregnancy. Hematopoiesis, the 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 adulthood, hematopoiesis takes place in the bone marrow. However, colonization of the bone marrow with primitive hematopoietic stem cells must occur during the 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 bone marrow development, resulting in a disruption of hematopoietic homeostasis and a decreased number of immune cells in the blood. Indeed, we have demonstrated that newborn mice exposed to nicotine during intrauterine development have a decreased immune response during the first month after birth. Furthermore, these mice had a lower number of hematopoietic stem cells which migrated in the bone marrow, compared to control animals. Based on our preliminary observations, we propose to investigate how nicotine can alter the ability of fetal hematopoietic stem cells to home in the fetal bone marrow. We found that within different cell types, nicotine can target endothelial cells and affect their ability to support extravasation (a migration from the blood stream into the tissues) of hematopoietic stem cells. We hypothesize that among other deleterious effects on fetal tissues, nicotine induces pathological changes in vascular function that might result in inferior colonization of fetal bone marrow by fetal hematopoietic stem cells. Thus, the proposed grant application fits the Cardiovascular Disease program and could significantly contribute to this TRDRP priority area of research. 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.

Publications

C3a and C5a are chemotactic factors for human mesenchymal stem cells, which cause prolonged ERK1/2 phosphorylation.
Periodical: Journal of Immunology			Index Medicus:
Authors: Schraufstatter IU, Discipio Rg, Zhao M, Khaldoyanidi S,				ART
Yr: 2009	Vol: 182	Nbr: 6	Abs:	Pg: 3827-3836

Hematopoietic differentiation of embryonic stem cells
Periodical: Methods			Index Medicus:
Authors: Orlovskaya I, Schraufstatter I, Loring J, Khaldoyanidi S				ART
Yr: 2008	Vol: 45	Nbr: 2	Abs:	Pg: 159-167

Directing stem cell homing
Periodical: Cell Stem Cell			Index Medicus:
Authors: Khaldoyanidi, S				ART
Yr: 2008	Vol: 2	Nbr: 3	Abs:	Pg: 198-200

Alpha 7 subunit on nARhR regulates migration of human mesenchymal stem cells.
Periodical: Journal of Stem Cells			Index Medicus:
Authors: Schraufstatter, IU; DiScipio, RG; Khaldoyanidi, S				ART
Yr: 2010	Vol: 4	Nbr:	Abs:	Pg: 203-216

Hyaluronan stimulates mobilization of mature hematopietic cells but not hematopoietic progenitors.
Periodical: Journal of Stem Cells			Index Medicus:
Authors: Schraufstatter, IU; Serobyan, N; DiScipio, R; Feofanova, N; Orlovskaya, S; Khaldoyanidi, S				ART
Yr: 2010	Vol: 4	Nbr:	Abs:	Pg: 191-202

Key players in the gene networks guiding ESCs toward mesoderm.
Periodical: Journal of Stem Cells			Index Medicus:
Authors: Omelyanchuk, N; Orlovskaya, IA; Schraufsatter, IU; Khaldoyanidi, S				ART
Yr: 2009	Vol: 4	Nbr:	Abs:	Pg: 147-160

C3a and C5a are chemotactic factors for human mesenchymal stem cells, which cause prolonged ERK1/2 phosphorylation.
Periodical: Journal of Immunology			Index Medicus:
Authors: Schraufstatter IU, Discipio Rg, Zhao M, Khaldoyanidi S,				ART
Yr: 2009	Vol: 182	Nbr: 6	Abs:	Pg: 3827-3836

Hematopoietic differentiation of embryonic stem cells
Periodical: Methods			Index Medicus:
Authors: Orlovskaya I, Schraufstatter I, Loring J, Khaldoyanidi S				ART
Yr: 2008	Vol: 45	Nbr: 2	Abs:	Pg: 159-167

Directing stem cell homing
Periodical: Cell Stem Cell			Index Medicus:
Authors: Khaldoyanidi, S				ART
Yr: 2008	Vol: 2	Nbr: 3	Abs:	Pg: 198-200

Alpha 7 subunit on nARhR regulates migration of human mesenchymal stem cells.
Periodical: Journal of Stem Cells			Index Medicus:
Authors: Schraufstatter, IU; DiScipio, RG; Khaldoyanidi, S				ART
Yr: 2010	Vol: 4	Nbr:	Abs:	Pg: 203-216

Hyaluronan stimulates mobilization of mature hematopietic cells but not hematopoietic progenitors.
Periodical: Journal of Stem Cells			Index Medicus:
Authors: Schraufstatter, IU; Serobyan, N; DiScipio, R; Feofanova, N; Orlovskaya, S; Khaldoyanidi, S				ART
Yr: 2010	Vol: 4	Nbr:	Abs:	Pg: 191-202

Key players in the gene networks guiding ESCs toward mesoderm.
Periodical: Journal of Stem Cells			Index Medicus:
Authors: Omelyanchuk, N; Orlovskaya, IA; Schraufsatter, IU; Khaldoyanidi, S				ART
Yr: 2009	Vol: 4	Nbr:	Abs:	Pg: 147-160