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1

Regulation of neurogenesis by extracellular matrix and integrins

100%
Wojcik-Stanaszek L., Gregor A., Zalewska T.
Acta Neurobiologiae Experimentalis
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2011
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tom 71
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nr 1
Deciphering the factors that regulate human neural stem cells will greatly aid in their use as models of development and as therapeutic agents. The complex interactions of cells with extracellular matrix (ECM) proteins probably contribute to proper central nervous system development mediating processes which regulate proliferation and differentiation of neural stem/rogenitor cells. Many of these interactions involve transmembrane integrin receptors. Integrins cluster in specific cell­matrix adhesions to provide dynamic links between extracellular and intracellular environments by activation of numerous signal transduction pathways which may influence cell behaviour profoundly by influence on both gene expression and post- transcriptional signalling cascade. In this review we introduced and discussed a number of extracellular and intracellular factors engaged in the transduction of signals induced by cell adhesion to its environment, including matrix components, extracellular proteolytic enzymes, integrins and non-receptor tyrosine kinases.
2

Effect of matrix metalloproteinases inhibition on the proliferation and differentiation of HUCB-NSCS cultured in the presence of adhesive substrates

100%
Szymczak P., Sypecka J., Wojcik-Stanaszek L., Zalewska T.
Acta Neurobiologiae Experimentalis
|
2011
|
tom 71
|
nr S
Cell adhesion to extracellular matrix (ECM) generates intracellular signals that modulate cell survival, proliferation, migration of neural precursor cells and differentiation in vitro. The function of ECM in developmental processes may be associated with particular patterns of proteolysis of ECM. Among the proteases the matrix metalloproteinases (MMPs) represent family of enzymes responsible for the modification of ECM components and by this may influence cell development. The aim of our study was to determine the potential of native ECM proteins: fibronectin, laminin and collagen, on the proliferation and differentiation of HUCB-NSCs cultured in serum free condition. In an effort to elucidate the engagement of MMPs we have checked the effect of inhibitors - SB-3CT, GM6001 and doxycycline on the above development-associated processes. Among the tested substrates the highest proliferation rate (evaluated by using anti-Ki67) was noted in the presence of fibronectin. Fibronectin also occurred most permissive substrate in HUCB-NSCs differentiation toward neuronal fate. The endogenous activity of MMPs (assayed by in situ zymography) corresponds to the rate of cell proliferation. Addition of MMPs inhibitors resulted in the significant suppression of proliferation potential and inhibition of neuronal cell generation (TUJ1- and MAP2-positive) with simultaneous promotion of oligo- and astroglial cells (expressing GALC and S100β, respectively). In conclusion, our results suggest that MMPs might be an important component in neurogenesis-associated processes. Supported by MSRHE grants: 0154/B/ P01/2010/38 and 0345/B/P01/2010/38.
3

Oxygen-glucose deprivation (OGD) promotes microglia activation and gliogenesis but not neurogenesis in organotypic hippocampal slice culture (OHC)

100%
Ziemka-Nalecz M., Wojcik-Stanaszek L., Zajac H., Zalewska T.
Acta Neurobiologiae Experimentalis
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2013
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tom 73
|
nr 1
Organotypic hippocampal cultures are used as an alternative model for studying molecular mechanism(s) of neurogenesis after combined oxygen-glucose deprivation (OGD) mimicking ischemic conditions. The aim of the present work was to investigate the effect of OGD on stem/progenitor cells proliferation and/or differentiation in the hippocampus. Our attention was primarily focused on the relationship between neurogenesis-associated processes and activity of matrix metalloproteinases (MMPs). Cell proliferation was detected by using BrdU incorporation. Newly generated BrdU (+) cells were identified by labeling with specific cell markers. In order to check the activity and localization of MMPs we conducted in situ zymography in conjunction with immunohistochemistry. In our experimental conditions OGD-insult followed by 24 h of recovery caused the damage of neuronal cells in CA1. At 1 week cell death appears all over the hippocampus. We found that expected stimulation of endogenous neurogenesis fails as a source of compensation for the lost neurons in OGD-treated cultures. The modulation of culture microenvironment after ischemia favors the dominant proliferation of glial cells expressed by the enhancement of newly-generated oligodendrocyte progenitors. In addition, during our study we also detected some BrdU labeled nuclei encapsulated by GFAP positive processes. However, the majority of BrdU positive cells expressed microglial specific stain, particularly pronounced in CAlarea. The OGD-promoted responses involved activation of metalloproteinases, which matches the progression of gliogenesis. On the other hand, the high activity of MMPs associated with microglial cells implicate their involvement in the mechanism participating in OGD-induced cell damage.
4

The potential role of FAK- and PYK2 coupled pathway in the neurogenesis in gerbil hippocampus after global ischemia

100%
Ziemka-Nalecz M., Wojcik-Stanaszek L., Zajac H., Zalewska T.
Acta Neurobiologiae Experimentalis
|
2011
|
tom 71
|
nr S
Recently published data indicate that in physiological conditions proteolytic remodeling of extracellular matrix (ECM) by matrix metalloproteinases (MMPs) participates in the stem cells development. Signal derived from ECM may activate specific intracellular signaling pathways which involve non-receptor tyrosine kinases such focal adhesion kinase (FAK) and proline-rich tyrosine kinase 2 (Pyk2), key components responsible for the flow of information to the cell. FAK and Pyk2 might act through a diverse array of downstream molecules such a phosphatidylinositol 3-kinase (PI3K)/Akt and extracellular signal-regulated kinase (ERK). Activation (PI3K)/ Akt and ERK pathways in neural precursors plays a central role in induction of adult neurogenesis. These prompted us to evaluate the possible involvement of FAK/PYK2-coupled pathway in the regulation of neurogenesis-associated processes stimulated by transient global ischemia in gerbil hippocampus. For this purpose we checked if there is temporal relationship between activation/phosphorylation of these kinases and proliferation and/or determination of neural progenitor cells. We found that short-term (5 min) ischemia increased Pyk-2 phosphorylation level in dentate gyrus ( neurogenic part of hippocampus) after 2 and 4 weeks of recovery, the time when we observed the intensive proliferation rate and differentiation of progenitors toward neuronal phenotypes. In contrast, in the CA1 region of the hippocampus the level of phosphorylated Pyk-2 was slightly reduced after 2, 4 and 6 weeks of reperfusion. At the same time the level of phosphorylated FAK was significantly increased in both investigated hippocampal regions. In contrast activation of ERK and Akt kinases was significantly reduced in all investigated time points with more pronounced effect in CA1. The elevation of PYK-2 activity in dentate gyrus might suggest the involvement of this kinase in the post-ischemic stimulation of neurogenesis after global ischemia.
5

FAK-and Pyk2-coupled pathway may contribute to the neurogenesis in gerbil hippocampus after ischemia

100%
Ziemka-Nalecz M., Wojcik-Stanaszek L., Zajac H., Zalewska T.
Acta Neurobiologiae Experimentalis
|
2011
|
tom 71
|
nr 1
Recently published data indicate that in physiological conditions proteolytic remodeling of extracellular matrix (ECM) by matrix metalloproteinases (MMPs) participates in the stem cells development. Signal derived from ECM may activate specific intracellular signaling pathways which involve non-receptor tyrosine kinases such focal adhesion kinase (FAK) and proline-rich tyrosine kinase 2 (Pyk2), key components responsible for their flow of information to the cell. The function of these enzymes is believed to be tightly linked to its autophosphorylation and association with Src kinase necessary for reciprocal activation/phosphorylation of both enzymes in response to adhesion-dependent signals. FAK and Pyk2 might act through a diverse array of downstream molecules and may regulate biological functions of the cell. These prompted us to evaluate the possible involvement of FAK/PYK2-coupled pathway in the regulation of neurogenesis-associated processes stimulated by transient global ischemia in gerbil hippocampus. For this purpose we checked if there is temporal relationship between activation/phosphorylation of both kinases and proliferation and/or determination of neural progenitor cells. We found that short-term (5 min) ischemia increased Pyk-2 phosphorylation level in dentate gyrus ( neurogenic part of hippocampus) after 2 and 4 weeks of recovery, the time when we observed the intensive proliferation rate and differentiation of progenitors toward neuronal phenotypes. In contrast, in the CA1 region of the hippocampus the level of phosphorylated Pyk-2 was slightly reduced after 2, 4 and 6 weeks of reperfusion. At the same time the level of phosphorylated FAK was significantly increased in both investigated hippocampal regions. The elevation of PYK-2 activity in dentate gyrus might suggest the involvement of this kinase in the post-ischemic stimulation of neurogenesis after global ischemia. Supported by MSHE grant no 0154/B/P01/2009/38.
6

Effect of matrix metalloproteinases inhibition on the proliferation and differentiation of HUCB-NSCs cultured in the presence of adhesive substrates

88%
Szymczak P., Wojcik-Stanaszek L., Sypecka J., Sokolowska A., Zalewska T.
Acta Neurobiologiae Experimentalis
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2010
|
tom 70
|
nr 4
Cell adhesion to extracellular matrix (ECM) generates intracellular signals that modulate cell survival, proliferation, migration and differentiation. Because of its heterogeneous nature, ECM has the potential to induce unique responses that are composition-dependent. One approach to study the effect of ECM signals on cell development, independently on signals from other extracellular sources, has been to deprive cells of serum and to analyze the influence of specific ligands. In the current work we determine the potential of different ECM proteins (fibronectin, laminin, collagen) on the proliferation and differentiation of human umbilical cord blood-derived neural stem cells (HUCB-NSCs) cultured in serum-free conditions. The effect of tested ECM components on the above processes might be associated with the particular pattern of their proteolysis. In this context enzymes that are responsible for the modification of ECM proteins are of particular pertinence. Matrix metalloproteinases (MMPs) represent a family of enzymes known to play role in the modification of ECM and by this can change the cell-ECM substrate interaction, required for cell development. In an effort to elucidate the participation of MMPs in the proliferation and differentiation HUCB-NSCs were cultured in the presence or absence of MMPs inhibitors – GM6001 and doxycycline. Our results show that addition of the above inhibitors interfered with both the proliferation and differentiation of progenitor cells toward the neuronal lineage. This effect depends on the adhesive ECM substrate and is most pronounced in the presence of fibronectin and laminin. In conclusion, our results suggest that MMPs modulate interaction between HUCB-NSCs and their environment and therefore might be an important component in neurogenesisassociated processes.
7

Potential role of MMP-2 and-9 in ischemia-stimulated neurogenesis in the gerbil hippocampus

88%
Wojcik-Stanaszek L., Szymczak P., Ziemka-Nalecz M., Zajac H., Zalewska T.
Acta Neurobiologiae Experimentalis
|
2011
|
tom 71
|
nr 1
Matrix metalloproteinases (MMPs) are a growing family of zincdependent endopeptidases that are classically recognized as matrixremodeling enzymes implicated in various physiological and pathological processes. Apart from relatively well established detrimental role of MMPs, in particular gelatinases (MMP-2 and MMP-9), following brain injury, MMPs have been considered recently to be involved in the neurogenic response of the adult neural stem/progenitor cells after ischemic challenge. However, the role of these enzymes in the neurogenesis still remains to be clarified. The goal of the present study was to elucidate if activation of MMPs parallels the rate of neural progenitor cells proliferation and/or further differentiation. Our results show that post-ischemic acceleration in the proliferation and differentiation of progenitors in the dentate gyrus of the adult hippocampus coincides with the remarkable elevation of MMPs activity. On the contrary, in the ischemia-damaged CA1 pyramidal cells layer the activity of MMPs fell below the control level. It should be pointed out, that in this structure neurogenesis seems to be rather elusive, as we did not found evidence for production of a new matured neurons. In an effort to further check the potential participation of MMPs in neurogenesis-associated processes we have tested the effect of MMPs inhibitors (GM6001 and doxycycline) on neural stem cells line. We observed that the addition of these agents decreased the rate of proliferation and differentiation toward neurons. In conclusion, the spatial and temporal profile of MMPs activity during reperfusion following transient forebrain ischemia suggest that these proteinases might belong to the discussed mechanism(s) which govern neurogenesis-associated processes in ischemic brain hippocampus. Supported by MSHE grant no 0154/B/P01/2009/38.
8

Intracerebral transplantation of human umbilical cord blood-derived neural stem cells (HUCB-NSC) in rats after focal brain ischemia ameliorates tissue expression of endogenous and exogenous neurotrophic factors

76%
Jablonska A., Drela K., Wojcik-Stanaszek L., Wanacka E., Zalewska T., Lukomska B.
Acta Neurobiologiae Experimentalis
|
2013
|
tom 73
|
nr 1
There is a great interest in the possibility of repairing the nervous system by transplantation new cells that can replace those lost through damage in neurological disorders. Key functions such as the replacement of neural cells have been recently challenged by intrinsic bystander capacities of undifferentiated donor cells to restore these cells. A comprehensive knowledge how transplanted stem cells exert their therapeutic achievements is still lacking. Here we investigated the effects of HUCB-NSC infused into the damaged rat brain at 72 h post ischemia on endogenous neurogenesis. The goal of our studies was to examine the proliferation and migration of host progenitor cells, analyze the substantial matrix remodeling of tissue and the presence of neurotrophic factors in rat brain after focal ischemia followed by HUCB-NSC transplantation. Methods: 2×104 HUCB-NSC were transplanted into corpus callosum of naive or focally injured rat brain 3 days after ischemic insult. At 1, 3, 7 and 14 days rat brains were removed. Endogenous cell proliferation was determined by BrdU incorporation. Then immunocytochemical analysis of doublecortin (DCX) and PSA-NCAM (markers expressed by immature migratory neuroblasts), and in situ zymography of MMPs activity was performed. Additionally, total RNA was isolated from rat brain tissue and RTPCR was performed using sets of primers of each of human and rat neurotrophic factor genes. Results: OUA-induced brain lesion resulted in increase of proliferating (BrdU+) and migrating (DCX+ and PSA-NCAM+) cells in subventricular zone (SVZ) and subgranular zone (SGZ) regions in comparison to intact rats. This response has been potentiated by HUCB-NSC transplantation. At 7th day after HUCB-NSC infusion the intense migration of DCX+cells from SVZ towards ischemic boundary regions of the striatum was observed. Moreover, the activation of MMPs in cells was visible in SVZ. Double-labeling showed co-localization of DCX marker with MMPs activity. The presence of MMPs appeared to be associated with cell nuclei and cytoplasm but interestingly it was also seen outside the cell bodies and in the neuronal protrusions. In OUAinduced lesion rat brain tissue, the expression pattern of rat-origin neurotrophic factors mRNA was higher than in intact rats. HUCBNSC transplantation into focal brain ischemic tissue significantly increased mRNA expression of several rat-origin growth factors, such as GDNF, CNTF responsible for regulation of proliferation and maturation of stem cells as well as IGF-1, HGF and presaposin functioning as anti-apoptotic mediators. The significant increment was observed 7 days after HUCB-NSC infusion. Using Real Time PCR method we were able to detect the presence of mRNA of BDNF, GDNF, NT3, IGF-1, HGF, semaphorin and presaposin of human-origin factors in the rat brain recipients of HUCB-NSC grafts. Conclusions: Transplantation of HUCB-NSC triggers early expansion of endogenous progenitor pool increasing fraction of proliferating cells in SVZ and SGZ of brain ischemic rats. Proteolytic activity of MMPs in extracellular compartment suggests its ability to remodel extracellular matrix and facilitate migration of neuroblasts to the damaged brain areas. The mechanism promoting recovery from ischemic injury remains to be clarified, although it is likely that it might be due to HUCB-NSC graft-induced release of neurotrophic factors by the host cells as well as the presence of human neural stem cells derived factors. Supported by MMRC statutory fund.
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