Publications
Here is a selection of publications where different laminin isoforms were used to create more authentic cell culture systems.
Laminin Alters Fyn Regulatory Mechanisms and Promotes Oligodendrocyte Development
Jenne Relucio, Iva D. Tzvetanova, Wei Ao, Sabine Lindquist and Holly Colognato. JNeurosci, 2009
The authors report that in laminin-deficient mice, oligodendrocyte progenitors accumulated inappropriately in adult brains. Laminin-211 was found to promote the transition of oligodendrocyte progenitors to newly formed oligodendrocytes. Laminin-enhanced differentiation was Src family kinase-dependent and resulted in the activation of the Src family kinase Fyn.
The extracellular matrix protein laminin α2 regulates the maturation and function of the blood-brain barrier
Michael J Menezes, Freyja K McClenahan, Cindy V Leiton, Azeez Aranmolate, Xiwei Shan, Holly Colognato. J Neurosc, 2014
In this article, Lama2(-/-) knock-out mice, lacking expression of the laminin α2 subunit of the laminin-211 heterotrimer expressed by astrocytes and pericytes, are shown to have defective blood-brain barrier (BBB ) in which systemically circulated tracer leaks into the brain parenchyma.
Laminins and Nidogens in the Pericellular Matrix of Chondrocytes - Their Role in Osteoarthritis and Chondrogenic Differentiation
Schminke B., Frese J., Bode C., Goldring M.B., Miosge N. American Society for Investigative Pathology, 2015
This is an investigation of cartilage tissue and isolated chondrocytes in three-dimensional culture obtained from patients with late-stage knee OA and nidogen-2 knockout mice. Chondrogenic progenitor cells (CPCs) produced high levels of laminin-a1, laminin-a5, and nidogen-2 in their pericellular matrix, and laminin-a1 enhanced collagen type II and reduced collagen type I expression by cultured CPCs. Nidogen-2 increased SOX9 gene expression. This study reveals that the influence of the pericellular matrix on CPCs is important for the expression of the major regulator transcription factors, SOX9 and RUNX2. Our novel findings that laminins and nidogen-2 drive CPCs toward chondrogenesis may help in the elucidation of new treatment strategies for cartilage tissue regeneration. In summary, the expression of nidogen-2 and laminin is increased in human OA cartilage, and they act as chondrogenic regulators, especially for CPCs. Laminin also promotes chondrogenesis, enhancing collagen type II, COMP, and aggrecan expression, and down-regulating collagen type I. Therefore, these findings on laminin and nidogen-2 may aid in the elucidation of new treatment options, especially for tissue regeneration.
Niche-derived laminin-511 promotes midbrain dopaminergic neuron survival and differentiation through YAP
Zhang D., Yang S., Toledo E.M., Gyllborg D., Saltó C., Villaescusa J.C., Arenas E.Sci Signal. 2017
The authors investigated the mechanisms controlling the survival of mDA neurons using embryonic and mDA neurons, midbrain tissue from mice, and differentiated human neural stem cells. The work identifies laminin511-YAP as a key pathway by which niche signals control the survival and differentiation of mDA neurons. Laminin alpha-5 is present in the extracellular matrix surrounding mDA neurons and indeed, the authors found laminin-511 promoted the survival and differentiation of mDA neurons via a novel pathway involving YAP, miR-130a, and PTEN. Laminin-511 bound to integrin a3b1 and activated the transcriptional cofactor YAP. Laminin511-YAP signaling enhanced cell survival by inducing the expression of the microRNA miR-130a, which suppressed the synthesis of the cell death–associated protein PTEN. In addition, laminin511-YAP signaling increased the expression of transcription factors critical for mDA identities, such as LMX1A and PITX3, and prevented the loss of mDA neurons in response to oxidative stress, a finding that warrants further investigation to assess the therapeutic potential for PD patients. The authors propose that by enhancing laminin511-YAP signaling, it may be possible to prevent mDA neuron degeneration in PD or enhance the survival of mDA neurons in cell replacement therapies.
β2 and γ3 laminins are critical cortical basement membrane components ablation of Lamb2 and Lamc3 genes disrupt cortical lamination and produces dysplasia
Radner S., Banos C., Bachay G., Li Y.N., Hunter D.D., Brunken W.J., Yee K.T.Developmental Neurobiology 2012
Here, the authors demonstrate the significance of laminin b2 and g3 expression in maintaining a functional cortical pial basement membrane to which Cajal Retzius and radial glial cells attach and in turn guide neural development. Several isoforms of laminins, those containing b2 and g3 in particular, have been isolated from the brain underlining their importance in CNS functions. In the present study, the authors employ a reverse genetic approach where mice with a homozygous deletion of b2 and g3 genes displayed cortical laminar disorganization. In addition, the ablation of both these laminin chains resulted in the incidence of human cobblestone lissencephaly. Interestingly, heterozygous mice also exhibited disruption of cortical neurons with lesser severity. In fact, similar to b2 distribution, g3 was also observed to be localized in the developing cortex. Mutation in the binding site of the laminin g1 gene results in abnormal cortex lamination.
Laminin/β1 integrin signal triggers axon formation by promoting microtubule assembly and stabilization
Lei W.L., Xing S.G., Deng C.Y., Ju X.C., Jiang X.Y., Luo Z.G.Cell Research 2012
In this study, the authors present several lines of evidence implicating the indispensable role of laminin in promoting neural polarization through integrin b1 (Itgb1) mediated microtubule assembly and stabilization. Laminin coated substrates (either in stripes or gradient) could initiate directional axon growth in undifferentiated neurites of both cultured hippocampal neurons and cortical slices in an Itgb1 dependent manner. Impairing endogenous laminin function either by treatment with exogenous laminins or by abolishing Itgb1 signaling using siRNA, resulted in defective axonal formation. Conditional knock out mice with abrogated Itgb1 expression in dorsal telencephalic progenitors displayed defective expression/activity of neuronal polarity related proteins, SAD and LKB1 kinases in addition to abnormal axonal development of cortical pyramidal neurons. These results not only identify laminin/ integrin b1 signaling as a crucial step in axon initiation and development but also link extracellular matrix adhesion to cytoskeleton remodeling that occurs during neuronal polarization.
Human diseases reveal novel roles for neural lamininsCortical deficiency of laminin γ1 impairs the AKT/GSK-3β signaling pathway and leads to defects in neurite outgrowth and neuronal migration
Chen Z.L., Haegeli V., Yu H., Strickland S.Developmental Biology, 2009
In this study, Chen and colleagues demonstrate the importance of laminin γ1 in the cerebral cortex and its absence leading to defects in neuritogenesis and neuronal migration. Mice lacking laminin γ1 gene expression suffered from disrupted cortical layers and impaired axonal pathfinding. Such loss during development has been shown to greatly affect the FAK and paxillin mediated integrin signaling mechanisms. Furthermore, mutant mice also display reduced phosphorylation of GSK-3β and AKT proteins. These data clearly show the participation of both integrin signaling and AKT/GSK-3β pathway in the regulation of neurite growth and neuronal migration by laminins.
Chronic stress induced disturbances in Laminin: a significant contributor to modulating microglial pro-inflammatory tone?
Pietrogrande G., Mabotuwana N., Zhao Z., Mahmoud A., Johnson S.J., Nilsson M., Walker F.R.Brain, Behavior, and Immunity, 2017.
In this study, Pietrogrande and colleagues have addressed the potential role of the extracellular matrix protein Laminin as a crucial factor to drive microglia into an inflamed state. Chronic restraint stress of C57BL6 adult mice over six weeks resulted in elevated levels of Laminin-α1 and pro-inflammatory markers such as TNF-α and iNOS, quantified by qPCR and western blot. Immunolabeling of Laminin-α1 identified pyramidal neurons and dentate gyrus to be their primary source within the hippocampus. Furthermore, Iba-1 staining of microglia revealed that chronic stress also strongly reduced the total branch length (15%), number of primary branches (47%) and number of branching points (68%) when compared to microglia of control mice. In vitro, primary microglia and BV2 cells grown on Laminin-111 expressed higher levels of TNF-α, IL-1β, and iNOS. In addition, LPS activation of microglia coated on Laminin-111 led to an increased pro-inflammatory state represented by higher pro-inflammatory cytokines level and phagocytic capability, both before and after stimulation. Interestingly, similar to observations made in vivo, microglia cultured on Laminin- 111 had fewer ramifications compared to control. These results, thus, expose the capability of chronic restraint stress in modulating Laminin within the CNS, an effect that has implications for understanding environmental mediated disturbances of microglial function.
Ablation of astrocytic laminin impairs vascular smooth muscle cell function and leads to hemorrhagic stroke
Chen Z-L., Yao Y., Norris E.H., Kruyer A., Jno-Charles O., Akhmerov A., Strickland S. J Cell Biol. 2013
Astrocytes express laminin-111 and 211 and assemble basement membranes (BMs) at their endfeet. Here the authors show that ablation of astrocytic laminin disrupted endfeet BMs and led to hemorrhage in deep brain regions of adult mice. The lack of astrocytic laminin led to impaired function of vascular smooth muscle cells, fragmentation and vascular wall disassembly where astrocytes have a closer association with VSMCs in small arterioles. Acute disruption of astrocytic laminin in the striatum of adult mice also impaired vascular smooth muscle cells function, indicating that laminin is necessary for vascular smooth muscle cell maintenance. In vitro, both astrocytes and astrocytic laminin promoted brain vascular smooth muscle cell differentiation.
Astrocytic laminin regulates pericyte differentiation and maintains blood-brain barrier integrity
Yao Y., Chen Z-L., Norris E.H., Strickland S.Nature comm, 2014
Here they show that lack of astrocytic laminin, a brain-specific BM component, induces BBB breakdown. Use conditional knockout mice and an acute adenovirus-mediated knockdown model. Using functional blocking antibody and RNAi, we further demonstrate that astrocytic laminin, by binding to integrin a2 receptor, prevents pericyte differentiation from the BBB-stabilizing resting stage to the BBB-disrupting contractile stage, and thus maintains the integrity of BBB. Loss of astrocytic laminin also decreases aquaporin-4 (AQP4) and tight junction protein expression. These results indicate that astrocytic laminin maintains the integrity of BBB through, at least in part, regulation of pericyte differentiation.