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Blood May 2022Impairment of normal hematopoiesis and leukemia progression are 2 well-linked processes during leukemia development and are controlled by the bone marrow (BM) niche....
Impairment of normal hematopoiesis and leukemia progression are 2 well-linked processes during leukemia development and are controlled by the bone marrow (BM) niche. Extracellular matrix proteins, including laminin, are important BM niche components. However, their role in hematopoiesis regeneration and leukemia is unknown. Laminin α4 (Lama4), a major receptor-binding chain of several laminins, is altered in BM niches in mice with acute myeloid leukemia (AML). So far, the impact of Lama4 on leukemia progression remains unknown. We here report that Lama4 deletion in mice resulted in impaired hematopoiesis regeneration following irradiation-induced stress, which is accompanied by altered BM niche composition and inflammation. Importantly, in a transplantation-induced MLL-AF9 AML mouse model, we demonstrate accelerated AML progression and relapse in Lama4-/- mice. Upon AML exposure, Lama4-/- mesenchymal stem cells (MSCs) exhibited dramatic molecular alterations, including upregulation of inflammatory cytokines that favor AML growth. Lama4-/- MSCs displayed increased antioxidant activities and promoted AML stem cell proliferation and chemoresistance to cytarabine, which was accompanied by increased mitochondrial transfer from the MSCs to AML cells and reduced reactive oxygen species in AML cells in vitro. Similarly, we detected lower levels of reactive oxygen species in AML cells from Lama4-/- mice post-cytarabine treatment. Notably, LAMA4 inhibition or knockdown in human MSCs promoted human AML cell proliferation and chemoprotection. Together, our study for the first time demonstrates the critical role of Lama4 in impeding AML progression and chemoresistance. Targeting Lama4 signaling pathways may offer potential new therapeutic options for AML.
Topics: Animals; Cytarabine; Drug Resistance, Neoplasm; Hematopoiesis; Humans; Laminin; Leukemia, Myeloid, Acute; Mesenchymal Stem Cells; Mice; Mice, Knockout; Reactive Oxygen Species
PubMed: 34958665
DOI: 10.1182/blood.2021011510 -
International Journal of Molecular... Dec 2021Decidualization is essential to the establishment of pregnancy in rodents and primates. Laminin A5 (encoding by ) is a member of the laminin family, which is mainly...
Decidualization is essential to the establishment of pregnancy in rodents and primates. Laminin A5 (encoding by ) is a member of the laminin family, which is mainly expressed in the basement membranes. Although laminins regulate cellular phenotype maintenance, adhesion, migration, growth, and differentiation, the expression, function, and regulation of laminin A5 during early pregnancy are still unknown. Therefore, we investigated the expression and role of laminin A5 during mouse and human decidualization. Laminin A5 is highly expressed in mouse decidua and artificially induced deciduoma. Laminin A5 is significantly increased under in vitro decidualization. Laminin A5 knockdown significantly inhibits the expression of , a marker for mouse decidualization. Progesterone stimulates the expression of laminin A5 in ovariectomized mouse uterus and cultured mouse stromal cells. We also show that progesterone regulates laminin A5 through the PKA-CREB-C/EBPβ pathway. Laminin A5 is also highly expressed in human pregnant decidua and cultured human endometrial stromal cells during in vitro decidualization. Laminin A5 knockdown by siRNA inhibits human in vitro decidualization. Collectively, our study reveals that laminin A5 may play a pivotal role during mouse and human decidualization via the PKA-CREB-C/EBPβ pathway.
Topics: Adult; Animals; CCAAT-Enhancer-Binding Protein-beta; Cyclic AMP; Cyclic AMP Response Element-Binding Protein; Cyclic AMP-Dependent Protein Kinases; Decidua; Female; Gene Expression Regulation, Developmental; Humans; Laminin; Male; Mice, Inbred ICR; Models, Biological; Pregnancy; Progesterone; Signal Transduction; Stromal Cells; Mice
PubMed: 35008625
DOI: 10.3390/ijms23010199 -
Trends in Cell Biology Dec 2019Basement membrane laminins (LNs) have been shown to modulate cellular phenotypes and differentiation both in vitro and during organogenesis in vivo. At least 16... (Review)
Review
Basement membrane laminins (LNs) have been shown to modulate cellular phenotypes and differentiation both in vitro and during organogenesis in vivo. At least 16 laminin isoforms are present in mammals, and most are available as recombinant proteins. Ubiquitous LN511 and LN521 promote the clonal derivation and expansion of pluripotent embryonic stem cells (ESCs), and, together with other highly cell type-specific laminins, they can support the differentiation of stem cells into, for example, cardiac muscle fibers, retinal pigmented epithelial (RPE) cells and photoreceptors, dopamine (DA) neurons, and skin keratinocytes. The laminin-supported differentiation methods are highly reproducible and can be made chemically defined and fully xeno-free - a prerequisite for preparing therapeutic stem cell-derived cells. In this review we describe recent work on the use of laminin-based cell culture matrices in stem cell differentiation.
Topics: Animals; Cell Differentiation; Embryonic Stem Cells; Humans; Keratinocytes; Laminin; Myocytes, Cardiac; Neurons; Organogenesis; Photoreceptor Cells, Vertebrate; Pluripotent Stem Cells; Retinal Pigment Epithelium; Stem Cell Niche
PubMed: 31703844
DOI: 10.1016/j.tcb.2019.10.001 -
Cell Adhesion & Migration 2013Laminins are large molecular weight glycoproteins constituted by the assembly of three disulfide-linked polypeptides, the α, β and γ chains. The human genome encodes... (Review)
Review
Laminins are large molecular weight glycoproteins constituted by the assembly of three disulfide-linked polypeptides, the α, β and γ chains. The human genome encodes 11 genetically distinct laminin chains. Structurally, laminin chains differ by the number, size and organization of a few constitutive domains, endowing the various members of the laminin family with common and unique important functions. In particular, laminins are indispensable building blocks for cellular networks physically bridging the intracellular and extracellular compartments and relaying signals critical for cellular behavior, and for extracellular polymers determining the architecture and the physiology of basement membranes.
Topics: Animals; Basement Membrane; Binding Sites; Cell Adhesion; Cell Adhesion Molecules; Extracellular Matrix; Humans; Laminin; Molecular Weight; Protein Conformation; Protein Folding; Protein Interaction Mapping; Protein Structure, Tertiary; Receptors, Laminin; Signal Transduction
PubMed: 23263632
DOI: 10.4161/cam.22826 -
Essays in Biochemistry Sep 2019Laminins are large cell-adhesive glycoproteins that are required for the formation and function of basement membranes in all animals. Structural studies by electron... (Review)
Review
Laminins are large cell-adhesive glycoproteins that are required for the formation and function of basement membranes in all animals. Structural studies by electron microscopy in the early 1980s revealed a cross-shaped molecule, which subsequently was shown to consist of three distinct polypeptide chains. Crystallographic studies since the mid-1990s have added atomic detail to all parts of the laminin heterotrimer. The three short arms of the cross are made up of continuous arrays of disulphide-rich domains. The globular domains at the tips of the short arms mediate laminin polymerization; the surface regions involved in this process have been identified by structure-based mutagenesis. The long arm of the cross is an α-helical coiled coil of all three chains, terminating in a cell-adhesive globular region. The molecular basis of cell adhesion to laminins has been revealed by recent structures of heterotrimeric integrin-binding fragments and of a laminin fragment bound to the carbohydrate modification of dystroglycan. The structural characterization of the laminin molecule is essentially complete, but we still have to find ways of imaging native laminin polymers at molecular resolution.
Topics: Animals; Binding Sites; Dystroglycans; Humans; Integrins; Laminin; Membrane Glycoproteins; Polymerization; Protein Binding; Protein Domains; Protein Multimerization
PubMed: 31092689
DOI: 10.1042/EBC20180075 -
Matrix Biology : Journal of the... Oct 2018Laminins are large heterotrimers composed of the α, β and γ subunits with distinct tissue-specific and developmentally regulated expression patterns. The laminin-α2... (Review)
Review
Laminins are large heterotrimers composed of the α, β and γ subunits with distinct tissue-specific and developmentally regulated expression patterns. The laminin-α2 subunit, encoded by the LAMA2 gene, is expressed in skeletal muscle, Schwann cells of the peripheral nerve and astrocytes and pericytes of the capillaries in the brain. Mutations in LAMA2 cause the most common type of congenital muscular dystrophies, called LAMA2 MD or MDC1A. The disorder manifests mostly as a muscular dystrophy but slowing of nerve conduction contributes to the disease. There are severe, non-ambulatory or milder, ambulatory variants, the latter resulting from reduced laminin-α2 expression and/or deficient laminin-α2 function. Lm-211 (α2β1γ1) is responsible for initiating basement membrane assembly. This is primarily accomplished by anchorage of Lm-211 to dystroglycan and α7β1 integrin receptors, polymerization, and binding to nidogen and other structural components. In LAMA2 MD, Lm-411 replaces Lm-211; however, Lm-411 lacks the ability to polymerize and bind to receptors. This results in a weakened basement membrane leading to the disease. The possibility of introducing structural repair proteins that correct the underlying abnormality is an attractive therapeutic goal. Recent studies in mouse models for LAMA2 MD reveal that introduction of laminin-binding linker proteins that restore lost functional activities can substantially ameliorate the disease. This review discusses the underlying mechanism of this repair and compares this approach to other developing therapies employing pharmacological treatments.
Topics: Animals; Basement Membrane; Dystroglycans; Humans; Integrins; Laminin; Membrane Glycoproteins; Mice; Muscular Dystrophies; Mutation; Protein Binding
PubMed: 29191403
DOI: 10.1016/j.matbio.2017.11.009 -
Molekuliarnaia Biologiia 2018Laminins are a family of extracellular heterotrimeric glycoproteins that are the main structural component of basement membranes (BMs), perform a barrier function, and... (Review)
Review
Laminins are a family of extracellular heterotrimeric glycoproteins that are the main structural component of basement membranes (BMs), perform a barrier function, and are important for adhesion, differentiation, migration, and resistance to apoptosis of various cells, including cancer cells. The review summarizes the current knowledge of how laminins produced by cancer and normal cells influence the key stages of carcinogenesis. Laminin 332 (LN-332) and LN-111 enhance proliferation of certain cancer cells and increase the tumour growth. LN-111 increases resistance to apoptosis, induces differentiation, and inhibits the epithelial-mesenchymal transition (EMT) of cancer cells. LN-332 is associated with higher adhesion and higher migration potential of cancer cells. LN-411 and LN-421 significantly increase motility of cancer cells. LN-332 and LN-511 facilitate cell-cell adhesion and affect the efficacy of cell-cell interactions. The laminin chains α4 and α5 are important for the development and function of blood and lymphatic vessels. The expression ratio of the α4 and α5 laminin chains defines the BM permeability to leukocytes and, presumably, cancer cells in blood and lymphatic vessels. Interactions between LN-511 and α2-containing laminins enhance self-renewal and survival of circulating cancer stem cells. Moreover, laminins are involved in the formation of premetastatic niches and new colonies. Endogenous expression of the α4 laminin chain stimulates proliferation of individualised circulating cancer cells in vitro and in vivo and facilitates micrometastasis.
Topics: Animals; Cell Movement; Humans; Laminin; Neoplasm Proteins; Neoplasms; Neoplastic Cells, Circulating
PubMed: 29989574
DOI: 10.7868/S0026898418030059 -
Cell Adhesion & Migration 2013Laminins, one of the major functional components of basement membranes, are found underlying endothelium, and encasing pericytes and smooth muscle cells in the vessel... (Review)
Review
Laminins, one of the major functional components of basement membranes, are found underlying endothelium, and encasing pericytes and smooth muscle cells in the vessel wall. Depending on the type of blood vessel (capillary, venule, postcapillary venule, vein or artery) and their maturation state, both the endothelial and mural cell phenotype vary, with associated changes in laminin isoform expression. Laminins containing the α4 and α5 chains are the major isoforms found in the vessel wall, with the added contribution of laminin α2 in larger vessels. We here summarize current data on the precise localization of these laminin isoforms and their receptors in the different layers of the vessel wall, and their potential contribution to vascular homeostasis.
Topics: Animals; Basement Membrane; Cell Differentiation; Dystroglycans; Endothelium, Vascular; Extracellular Matrix; Fluorescent Antibody Technique; Humans; Laminin; Mechanotransduction, Cellular; Mice; Muscle Contraction; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Phenotype; Protein Isoforms; Receptors, Laminin
PubMed: 23263631
DOI: 10.4161/cam.22680 -
Trends in Immunology Nov 2017Laminins are trimeric proteins that are major components of the basement membranes that separate endothelia and epithelia from the underlying tissue. Sixteen laminin... (Review)
Review
Laminins are trimeric proteins that are major components of the basement membranes that separate endothelia and epithelia from the underlying tissue. Sixteen laminin isoforms have been described, each with distinct tissue expression patterns and functions. While laminins have a critical structural role, recent evidence also indicates that they also impact the migration and functions of immune cells. Laminins are differentially expressed upon immunity or tolerance and orientate the immune response. This review will summarize the structure of laminins, the modulation of their expression, and their interactions with the immune system. Finally, the role of the laminins in autoimmune diseases and transplantation will be discussed.
Topics: Animals; Autoimmune Diseases; Basement Membrane; Cell Movement; Epithelial-Mesenchymal Transition; Gene Expression Regulation; Humans; Immune System; Immune Tolerance; Immunity; Laminin; Lymphocytes; Protein Isoforms; Transcriptome; Transplantation Immunology
PubMed: 28684207
DOI: 10.1016/j.it.2017.06.002 -
The International Journal of... Mar 1993The mouse embryonal carcinoma lines PCC4-F and F9 have played important roles in the isolation and characterization of the two ubiquitous basement membrane proteins,... (Review)
Review
The mouse embryonal carcinoma lines PCC4-F and F9 have played important roles in the isolation and characterization of the two ubiquitous basement membrane proteins, laminin and entactin. The contributions of these cells to our work on extracellular matrices are briefly summarized. The in vitro differentiation of PCC4-F gives rise to a multiplicity of cell types. Two of these cell types have been propagated as cell lines. One of these, M1536-B3, synthesizes and deposits copious quantities of extracellular matrix glycoproteins, which led to the initial discovery and characterization of laminin and entactin. In addition, M1536-B3 provides a model system for analyzing the assembly of laminin and the laminin-entactin complex and for manipulating extracellular matrix structure and composition. The other cell line, 4CQ, synthesizes a matrix consisting of fibronectin and entactin. F9 cells differentiate to endodermal cells in response to retinoic acid and dibutyryl cyclic AMP (Strickland and Mahdavi, Cell 15: 393-402, 1978). The differentiated cells synthesize basement membrane components and provided the probes for the cDNA cloning of entactin and the three chains of laminin. The F9 cells have been widely employed to examine the regulation of expression of the laminin and entactin genes.
Topics: Animals; Basement Membrane; Laminin; Membrane Glycoproteins; Mice; Neoplasm Proteins; Teratoma
PubMed: 8507559
DOI: No ID Found