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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 -
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 -
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 -
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 -
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 -
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 -
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 -
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 -
European Cells & Materials Jul 2017As a key molecule of the extracellular matrix, laminin provides a delicate microenvironment for cell functions. Recent findings suggest that laminins expressed by... (Review)
Review
As a key molecule of the extracellular matrix, laminin provides a delicate microenvironment for cell functions. Recent findings suggest that laminins expressed by cartilage-forming cells (chondrocytes, progenitor cells and stem cells) could promote chondrogenesis. However, few papers outline the effect of laminins on providing a favorable matrix microenvironment for cartilage regeneration. In this review, we delineated the expression of laminins in hyaline cartilage, fibrocartilage and cartilage-like tissue (nucleus pulposus) throughout several developmental stages. We also examined the effect of laminins on the biological activities of chondrocytes, including adhesion, migration and survival. Furthermore, we scrutinized the potential influence of various laminin isoforms on cartilage-forming cells' proliferation and chondrogenic differentiation. With this information, we hope to facilitate the understanding of the spatial and temporal interactions between cartilage-forming cells and laminin microenvironment to eventually advance cell-based cartilage engineering and regeneration.
Topics: Animals; Cartilage, Articular; Cell Proliferation; Chondrocytes; Chondrogenesis; Humans; Laminin; Regeneration
PubMed: 28731483
DOI: 10.22203/eCM.v034a03 -
Biochemical Society Transactions Dec 2022Basement membranes (BMs) are structured regions of the extracellular matrix that provide multiple functions including physical support and acting as a barrier, as a...
Basement membranes (BMs) are structured regions of the extracellular matrix that provide multiple functions including physical support and acting as a barrier, as a repository for nutrients and growth factors, and as biophysical signalling hubs. At the core of all BMs is the laminin (LM) family of proteins. These large heterotrimeric glycoproteins are essential for tissue integrity, and differences between LM family members represent a key nexus in dictating context and tissue-specific functions. These variations reflect genetic diversity within the family, which allows for multiple structurally and functionally distinct heterotrimers to be produced, each with different architectures and affinities for other matrix proteins and cell surface receptors. The ratios of these LM isoforms also influence the biophysical properties of a BM owing to differences in their relative ability to form polymers or networks. Intriguingly, the LM superfamily is further diversified through the related netrin family of proteins and through alternative splicing leading to the generation of non-LM short proteins known as the laminin N-terminus (LaNt) domain proteins. Both the netrins and LaNt proteins contain structural domains involved in LM-to-LM interaction and network assembly. Emerging findings indicate that one netrin and at least one LaNt protein can potently influence the structure and function of BMs, disrupting the networks, changing physical properties, and thereby influencing tissue function. These findings are altering the way that we think about LM polymerisation and, in the case of the LaNt proteins, suggest a hitherto unappreciated form of LM self-regulation.
Topics: Laminin; Basement Membrane; Protein Isoforms; Alternative Splicing; Extracellular Matrix
PubMed: 36355367
DOI: 10.1042/BST20210240