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Communications Biology Dec 2021Organoids-cellular aggregates derived from stem or progenitor cells that recapitulate organ function in miniature-are of growing interest in developmental biology and... (Review)
Review
Organoids-cellular aggregates derived from stem or progenitor cells that recapitulate organ function in miniature-are of growing interest in developmental biology and medicine. Organoids have been developed for organs and tissues such as the liver, gut, brain, and pancreas; they are used as organ surrogates to study a wide range of questions in basic and developmental biology, genetic disorders, and therapies. However, many organoids reported to date have been cultured in Matrigel, which is prepared from the secretion of Engelbreth-Holm-Swarm mouse sarcoma cells; Matrigel is complex and poorly defined. This complexity makes it difficult to elucidate Matrigel-specific factors governing organoid development. In this review, we discuss promising Matrigel-free methods for the generation and maintenance of organoids that use decellularized extracellular matrix (ECM), synthetic hydrogels, or gel-forming recombinant proteins.
Topics: Animals; Biocompatible Materials; Collagen; Decellularized Extracellular Matrix; Drug Combinations; Humans; Hydrogels; Laminin; Mice; Organoids; Proteoglycans; Tissue Culture Techniques
PubMed: 34893703
DOI: 10.1038/s42003-021-02910-8 -
The Journal of Clinical Investigation Aug 2021Patients with neuropathic pain often experience comorbid psychiatric disorders. Cellular plasticity in the anterior cingulate cortex (ACC) is assumed to be a critical...
Patients with neuropathic pain often experience comorbid psychiatric disorders. Cellular plasticity in the anterior cingulate cortex (ACC) is assumed to be a critical interface for pain perception and emotion. However, substantial efforts have thus far been focused on the intracellular mechanisms of plasticity rather than the extracellular alterations that might trigger and facilitate intracellular changes. Laminin, a key element of the extracellular matrix (ECM), consists of one α-, one β-, and one γ-chain and is implicated in several pathophysiological processes. Here, we showed in mice that laminin β1 (LAMB1) in the ACC was significantly downregulated upon peripheral neuropathy. Knockdown of LAMB1 in the ACC exacerbated pain sensitivity and induced anxiety and depression. Mechanistic analysis revealed that loss of LAMB1 caused actin dysregulation via interaction with integrin β1 and the subsequent Src-dependent RhoA/LIMK/cofilin pathway, leading to increased presynaptic transmitter release probability and abnormal postsynaptic spine remodeling, which in turn orchestrated the structural and functional plasticity of pyramidal neurons and eventually resulted in pain hypersensitivity and anxiodepression. This study sheds new light on the functional capability of ECM LAMB1 in modulating pain plasticity and identifies a mechanism that conveys extracellular alterations to intracellular plasticity. Moreover, we identified cingulate LAMB1/integrin β1 signaling as a promising therapeutic target for the treatment of neuropathic pain and associated anxiodepression.
Topics: Animals; Anxiety; Behavior, Animal; Depression; Female; Gene Knockdown Techniques; Gyrus Cinguli; Laminin; Mice; Neuralgia; Peripheral Nervous System Diseases
PubMed: 34156983
DOI: 10.1172/JCI146323 -
Nature Cancer Jan 2022Although dormancy is thought to play a key role in the metastasis of breast tumor cells to the brain, our knowledge of the molecular mechanisms regulating disseminated...
Although dormancy is thought to play a key role in the metastasis of breast tumor cells to the brain, our knowledge of the molecular mechanisms regulating disseminated tumor cell (DTC) dormancy in this organ is limited. Here using serial intravital imaging of dormant and metastatic triple-negative breast cancer lines, we identify escape from the single-cell or micrometastatic state as the rate-limiting step towards brain metastasis. We show that every DTC occupies a vascular niche, with quiescent DTCs residing on astrocyte endfeet. At these sites, astrocyte-deposited laminin-211 drives DTC quiescence by inducing the dystroglycan receptor to associate with yes-associated protein, thereby sequestering it from the nucleus and preventing its prometastatic functions. These findings identify a brain-specific mechanism of DTC dormancy and highlight the need for a more thorough understanding of tumor dormancy to develop therapeutic approaches that prevent brain metastasis.
Topics: Astrocytes; Brain; Brain Neoplasms; Breast Neoplasms; Female; Humans; Laminin; Tumor Microenvironment
PubMed: 35121993
DOI: 10.1038/s43018-021-00297-3 -
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 -
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 -
Glia Mar 2022Oligodendrocytes are the cells that myelinate axons and provide trophic support to neurons in the CNS. Their dysfunction has been associated with a group of disorders... (Review)
Review
Oligodendrocytes are the cells that myelinate axons and provide trophic support to neurons in the CNS. Their dysfunction has been associated with a group of disorders known as demyelinating diseases, such as multiple sclerosis. Oligodendrocytes are derived from oligodendrocyte precursor cells, which differentiate into premyelinating oligodendrocytes and eventually mature oligodendrocytes. The development and function of oligodendrocytes are tightly regulated by a variety of molecules, including laminin, a major protein of the extracellular matrix. Accumulating evidence suggests that laminin actively regulates every aspect of oligodendrocyte biology, including survival, migration, proliferation, differentiation, and myelination. How can laminin exert such diverse functions in oligodendrocytes? It is speculated that the distinct laminin isoforms, laminin receptors, and/or key signaling molecules expressed in oligodendrocytes at different developmental stages are the reasons. Understanding molecular targets and signaling pathways unique to each aspect of oligodendrocyte biology will enable more accurate manipulation of oligodendrocyte development and function, which may have implications in the therapies of demyelinating diseases. Here in this review, we first introduce oligodendrocyte biology, followed by the expression of laminin and laminin receptors in oligodendrocytes and other CNS cells. Next, the functions of laminin in oligodendrocyte biology, including survival, migration, proliferation, differentiation, and myelination, are discussed in detail. Last, key questions and challenges in the field are discussed. By providing a comprehensive review on laminin's roles in OL lineage cells, we hope to stimulate novel hypotheses and encourage new research in the field.
Topics: Cell Differentiation; Laminin; Myelin Sheath; Neurogenesis; Oligodendrocyte Precursor Cells; Oligodendroglia
PubMed: 34773273
DOI: 10.1002/glia.24117 -
Science (New York, N.Y.) Nov 2021The signaling of cells by scaffolds of synthetic molecules that mimic proteins is known to be effective in the regeneration of tissues. Here, we describe peptide...
The signaling of cells by scaffolds of synthetic molecules that mimic proteins is known to be effective in the regeneration of tissues. Here, we describe peptide amphiphile supramolecular polymers containing two distinct signals and test them in a mouse model of severe spinal cord injury. One signal activates the transmembrane receptor β1-integrin and a second one activates the basic fibroblast growth factor 2 receptor. By mutating the peptide sequence of the amphiphilic monomers in nonbioactive domains, we intensified the motions of molecules within scaffold fibrils. This resulted in notable differences in vascular growth, axonal regeneration, myelination, survival of motor neurons, reduced gliosis, and functional recovery. We hypothesize that the signaling of cells by ensembles of molecules could be optimized by tuning their internal motions.
Topics: Animals; Cell Survival; Computer Simulation; Human Umbilical Vein Endothelial Cells; Humans; Integrin beta1; Laminin; Mice; Motor Neurons; Nanofibers; Neovascularization, Physiologic; Neural Stem Cells; Peptides; Peptidomimetics; Polymers; Protein Conformation, beta-Strand; Receptor, Fibroblast Growth Factor, Type 2; Recovery of Function; Signal Transduction; Spinal Cord Injuries; Spinal Cord Regeneration; Surface-Active Agents; Tissue Scaffolds
PubMed: 34762454
DOI: 10.1126/science.abh3602 -
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 -
Journal of Cerebral Blood Flow and... Nov 2022Laminin, a major component of the basal lamina (BL), is a heterotrimeric protein with many isoforms. In the CNS, laminin is expressed by almost all cell types, yet... (Review)
Review
Laminin, a major component of the basal lamina (BL), is a heterotrimeric protein with many isoforms. In the CNS, laminin is expressed by almost all cell types, yet different cells synthesize distinct laminin isoforms. By binding to its receptors, laminin exerts a wide variety of important functions. However, due to the reciprocal and cell-specific expression of laminin in different cells at the neurovascular unit, its functions in blood-brain barrier (BBB) maintenance and BBB repair after injury are not fully understood. In this review, we focus on the expression and functions of laminin and its receptors in the neurovascular unit under both physiological and pathological conditions. We first briefly introduce the structures of laminin and its receptors. Next, the expression and functions of laminin and its receptors in the CNS are summarized in a cell-specific manner. Finally, we identify the knowledge gap in the field and discuss key questions that need to be answered in the future. Our goal is to provide a comprehensive overview on cell-specific expression of laminin and its receptors in the CNS and their functions on BBB integrity.
Topics: Basement Membrane; Biological Transport; Blood-Brain Barrier; Laminin; Receptors, Laminin
PubMed: 35796497
DOI: 10.1177/0271678X221113027 -
Tissue & Cell Feb 2019The interactions between cells and the extracellular matrix (ECM) play a major role in normal and pathological conditions. The ECM can modulate several biological... (Review)
Review
The interactions between cells and the extracellular matrix (ECM) play a major role in normal and pathological conditions. The ECM can modulate several biological functions including cell proliferation, adhesion, differentiation and survival through its interactions with cell receptors. Laminins are one of the most important glycoproteins present in basement membranes, a type of ECM. The pattern of expression of its different isoforms depends on the spatiotemporal organization of each tissue. While integrins are the most studied laminin receptors, other non-integrin laminin receptors are also involved. This review focuses on two particular non-integrin laminin receptors in the epithelial context: dystroglycan and 37/67 laminin receptor (37/67LR). Dystroglycan is a two-subunit protein discovered in the muscle as part of the dystrophin-associated glycoprotein complex. This protein can also be found in many epithelia where its roles are variable. The 37/67LR is a still incompletely understood laminin receptor that is important to regulate intestinal epithelial cell function and could be involved in various pathological conditions.
Topics: Basement Membrane; Cell Differentiation; Cell Proliferation; Dystroglycans; Epithelial Cells; Epithelium; Extracellular Matrix; Humans; Integrins; Laminin; Receptors, Laminin
PubMed: 30736907
DOI: 10.1016/j.tice.2018.12.005