The diverse role of laminin isoforms in neuronal cells, human mast cells and blood platelets
Author: Sime, Wondossen
Date: 2007-02-23
Location: Westinrummet (Westin, plan 7), Odontologiska Institutionen, Huddinge
Time: 09.30
Department: Institutionen för odontologi / Department of Odontology
View/ Open:
thesis.pdf (1.289Mb)
Abstract
The close interaction of cells with other cells and with extracellular
matrix (ECM) components is a prerequisite in a number of biological
activities. During development of the nervous system, axons often
navigate a considerable distance depending on the type of molecular
factors they encounter. Similarly, precursor and mature cells of
haematopoietic origin home to specific locations during inflammation,
wound healing, immune responses and thrombosis. Laminins (LMs), major
components of specialized ECMs known as basement membranes, are large
heterotrimeric glycoproteins made of alphabetagamma subunits. To date,
5alpha, 3beta, and 3gamma chains have been identified, which by
combination yield at least 15 different LM isoforms. These isoforms have
a cell-and tissue-specific expression and are recognized by several
integrins. The functional role of laminin isoforms has not been fully
explored as the majority of early studies focused on LM-111
(alpha1beta1gamma1, laminin-1), the first laminin to be identified. The
work presented in this thesis was therefore designed primarily to address
synthesis, expression and, particularly, function of laminin isoforms in
different cell types.
First, we showed synthesis and expression of LM-211 (alpha2beta1gamma1,
laminin-2) and LM-411 (alpha4beta1gamma1, laminin-8) w by tooth pulp
fibroblasts based on RT-PCR, FACS, immunoprecipitation and Western blot
analysis. In functional studies, LM-411, unlike LM-211, was shown to
strongly promote neurite outgrowth from sensory trigeminal ganglion (TG)
neurons. This activity may be relevant to tooth innervation.
In a following study, strong adhesion and migration promoting activities
of alpha3-and alpha5-LMs, but not of alpha1-, alpha2- and alpha4-LMs, for
human mast cells (CBMCs and HMC.1) were demonstrated. Among the different
laminin-binding integrins, alpha3beta1 mediated the cell adhesion and
migration. HMC-1 cells expressed transcripts for LM alpha5, beta1 and
gamma1 and, following stimulation, secreted the corresponding
heterotrimer LM-511 (alpha5beta1gamma1). These findings demonstrated the
pivotal role of alpha3- and alpha5-LMs and their alpha3beta1 integrin
receptor in mast cell adhesion and migration, and may explain the
characteristic tissue localization of these immune cells in close
apposition to epithelial, vascular and neural basement membranes.
Synthesis of laminins by erythromegakaryocytic cell lines and their
secretion by blood platelets were also investigated. Other than detecting
transcripts for LM alpha3, alpha5, beta1, beta2, and gamma1 in the cell
lines, presence of fully heterotrimeric alpha-3 (LM-311 and LM-321) and
alpha-5 (LM-511 and LM-521) laminins was demonstrated in these cells as
well as in platelets. Both alpha3- and alpha5-LMs were secreted by the
platelets following stimulation. Functional studies showed that LM-511
(Lm-10) was the most platelet adhesive isoform followed by LM-411 (LM-8),
LM-332 (LM-5) and LM-111 (LM-1). This adhesion was largely mediated by
alpha6beta1 integrin. In spite of their adhesive properties, LM-332,
LM-411 and LM-511 induced neither P-selectin expression nor cell
aggregation, two signs of platelet activation. In addition, we reported
expression of alpha3-LMs in blood vessels of skin, gingiva, lymph nodes
and other tissues, mainly as LM-311 and/or LM-321. Moreover, migration
promoting and platelet-like particle forming activities of major vascular
laminin isoforms LM-411 and LM-511 were demonstrated on in vitro
differentiated CD41+ megakaryocytes, in comparison to other laminin
isoforms. Thus, vascular laminins may contribute, when exposed to the
circulation, to platelet adhesion but not activation and, in bone marrow,
to megakaryocyte migration and platelet formation.
Altogether, this thesis work illustrates the diverse functional role of
laminin isoforms in different cell types.
List of papers:
I. Fried K, Sime W, Lillesaar C, Virtanen I, Tryggvasson K, Patarroyo M (2005). "Laminins 2 (alpha2beta1gamma1, Lm-211) and 8 (alpha4beta1gamma1, Lm-411) are synthesized and secreted by tooth pulp fibroblasts and differentially promote neurite outgrowth from trigeminal ganglion sensory neurons" Exp Cell Res 307(2): 329-41
Pubmed
II. Sime W, Lunderious C, Kramer R, Rousselle P, Nilsson G, Patarroyo M (2007). "The selective role of laminin-332 (Lm-5) and laminin-511 (Lm-10) and their integrin receptor alpha3beta1 in human mast cell adhesion and migration." (Manuscript)
III. Nigatu A, Sime W, Gorfu G, Geberhiwot T, Anduren I, Ingerpuu S, Doi M, Tryggvason K, Hjemdahl P, Patarroyo M (2006). "Megakaryocytic cells synthesize and platelets secrete alpha5-laminins, and the endothelial laminin isoform laminin 10 (alpha5beta1gamma1) strongly promotes adhesion but not activation of platelets" Thromb Haemost 95(1): 85-93
Pubmed
IV. Sime W, Virtanen I, Anduren I, Ingerpuu S, Rousselle P, Smirnov S, Yurchenco P, Jones JCR, Domogatskaya A, Tryggvasson K, Nilsson G, Hjemdahl P, Patarroyo M (2007). "Expression of alpha3-laminins by platelets and blood vessels and their role in promoting platelet adhesion, megakaryocyte migration and platelet formation in comparison to other laminin isoforms." (Manuscript)
I. Fried K, Sime W, Lillesaar C, Virtanen I, Tryggvasson K, Patarroyo M (2005). "Laminins 2 (alpha2beta1gamma1, Lm-211) and 8 (alpha4beta1gamma1, Lm-411) are synthesized and secreted by tooth pulp fibroblasts and differentially promote neurite outgrowth from trigeminal ganglion sensory neurons" Exp Cell Res 307(2): 329-41
Pubmed
II. Sime W, Lunderious C, Kramer R, Rousselle P, Nilsson G, Patarroyo M (2007). "The selective role of laminin-332 (Lm-5) and laminin-511 (Lm-10) and their integrin receptor alpha3beta1 in human mast cell adhesion and migration." (Manuscript)
III. Nigatu A, Sime W, Gorfu G, Geberhiwot T, Anduren I, Ingerpuu S, Doi M, Tryggvason K, Hjemdahl P, Patarroyo M (2006). "Megakaryocytic cells synthesize and platelets secrete alpha5-laminins, and the endothelial laminin isoform laminin 10 (alpha5beta1gamma1) strongly promotes adhesion but not activation of platelets" Thromb Haemost 95(1): 85-93
Pubmed
IV. Sime W, Virtanen I, Anduren I, Ingerpuu S, Rousselle P, Smirnov S, Yurchenco P, Jones JCR, Domogatskaya A, Tryggvasson K, Nilsson G, Hjemdahl P, Patarroyo M (2007). "Expression of alpha3-laminins by platelets and blood vessels and their role in promoting platelet adhesion, megakaryocyte migration and platelet formation in comparison to other laminin isoforms." (Manuscript)
Issue date: 2007-02-02
Rights:
Publication year: 2007
ISBN: 978-91-7357-122-7
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