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PubMed2004

NFAT5/TonEBP mutant mice define osmotic stress as a critical feature of the lymphoid microenvironment.

Osmotic stress responses are critical not only to the survival of unicellular organisms but also to the normal function of the mammalian kidney. However, the extent to which cells outside the kidney rely on osmotic stress responses in vivo remains unknown. Nuclear factor of activated T cells 5 (NFAT5)/tonicity enhancer binding protein (TonEBP), the only known osmosensitive mammalian transcription factor, is expressed most abundantly in the thymus and is induced upon lymphocyte activation. Here we report that NFAT5/TonEBP is not only essential for normal cell proliferation under hyperosmotic conditions but also necessary for optimal adaptive immunity. Targeted deletion of exons 6 and 7 of the Nfat5 gene, which encode a critical region of the DNA-binding domain, gave rise to a complete loss of function in the homozygous state and a partial loss of function in the heterozygous state. Complete loss of function resulted in late gestational lethality. Furthermore, hypertonicity-induced NFAT5/TonEBP transcriptional activity and hsp70.1 promoter function were completely eliminated, and cell proliferation under hyperosmotic culture conditions was markedly impaired. Partial loss of NFAT5/TonEBP function resulted in lymphoid hypocellularity and impaired antigen-specific antibody responses in viable heterozygous animals. In addition, lymphocyte proliferation ex vivo was reduced under hypertonic, but not isotonic, culture conditions. Direct measurement of tissue osmolality further revealed lymphoid tissues to be hyperosmolar. These results indicate that lymphocyte-mediated immunity is contingent on adaptation to physiologic osmotic stress, thus providing insight into the lymphoid microenvironment and the importance of the NFAT5/TonEBP osmotic stress response pathway in vivo.

Animals↗

PubMed2006

Anisotropy of cell adhesive microenvironment governs cell internal organization and orientation of polarity.

Control of the establishment of cell polarity is an essential function in tissue morphogenesis and renewal that depends on spatial cues provided by the extracellular environment. The molecular role of cell-cell or cell-extracellular matrix (ECM) contacts on the establishment of cell polarity has been well characterized. It has been hypothesized that the geometry of the cell adhesive microenvironment was directing cell surface polarization and internal organization. To define how the extracellular environment affects cell polarity, we analyzed the organization of individual cells plated on defined micropatterned substrates imposing cells to spread on various combinations of adhesive and nonadhesive areas. The reproducible normalization effect on overall cell compartmentalization enabled quantification of the spatial organization of the actin network and associated proteins, the spatial distribution of microtubules, and the positioning of nucleus, centrosome, and Golgi apparatus. By using specific micropatterns and statistical analysis of cell compartment positions, we demonstrated that ECM geometry determines the orientation of cell polarity axes. The nucleus-centrosome orientations were reproducibly directed toward cell adhesive edges. The anisotropy of the cell cortex in response to the adhesive conditions did not affect the centrosome positioning at the cell centroid. Based on the quantification of microtubule plus end distribution we propose a working model that accounts for that observation. We conclude that, in addition to molecular composition and mechanical properties, ECM geometry plays a key role in developmental processes.

Anisotropy↗

PubMed1977

Calcium modulation in brain extracellular microenvironment demonstrated with ion-selective micropipette.

Changes in extracellular Ca2+ concentration were directly measured in the rat cerebellum, using an ion-selective micropipette. Extracellular K+ was measured simultaneously with a second ion-selective micropipette. The potential reference barrels of the ion electrodes also provided fast field and slow potentials. During repetitive stimulation of the parallel fiber--Purkinje cell cerebellar circuit, extracellular Ca2+ fell to about 80% of base line concentration. During the spreading depression of Leão, extracellular Ca2+ fell to about 10% of base line; decreases of this magnitude also occurred during terminal anoxia. In all cases extracellular K+ increased substantially. These results show that extracellular Ca2+ is modulated during neuronal activity in the central nervous system and that under some conditions the Ca2+ change can be extreme. Given the well-established and antagonistic effects of reduce extracellular Ca2+ on axonal excitability and synaptic transmission, these results suggest that Ca2+ modulation in the brain cell microenvironment may be a significant parameter in the behavior of neuronal ensembles.

Animals↗

PubMed1990

The microenvironment created by grafting rostral half-somites is mitogenic for neural crest cells.

Chicken embryo neural crest cells that migrate into a paraxial mesoderm constructed of multiple rostral half-somites from quail embryos form unsegmented "polyganglia," instead of distinct dorsal root ganglia (DRG). We report here that the environment that is created by grafting rostral somitic (RS) moieties not only is permissive for neural crest cell migration and consequent DRG formation but also is mitogenic for the DRG precursor cells. On embryonic day 3.5 (E3.5), 1 day after surgery, there is a 42% average increase in volume of the polyganglia compared with the corresponding DRG on the unoperated side. The volume increase is accounted for by an increased number of DRG cells--an average of 46% more cells are found in the polyganglia. The increases in volume and cell number are still present a day later at E4.5 (38% and 52%, respectively) and are observed in both limb-forming and non-limb-forming regions of the embryonic axis. The mechanism for this increase in cell number and volume in the polyganglia is enhanced proliferative activity. On E3.5 the proportion of cells incorporating thymidine of the total DRG cell number is 45% higher in the polyganglia than the control side, when embryos are given a short pulse before sacrifice. This indicates that rostral sclerotomal environment stimulates the crest cells to proliferate. The difference in volume between the polyganglia and the normal DRG continues to grow until at least E8, when the polyganglia are twice as large as the control DRG. The continued increase in volume can also be accounted for by the mitogenic effect of the RS grafts, since on E4.5 the percentage of thymidine-labeled cells compared with the total cell number in DRG is 28% higher in the polyganglia than in control ganglia. This study demonstrates that the somitic microenvironment regulates the proliferation of neural crest cells in the nascent DRG.

Animals↗

PubMed1990

Origin of osteoclasts: mature monocytes and macrophages are capable of differentiating into osteoclasts under a suitable microenvironment prepared by bone marrow-derived stromal cells.

We previously reported that osteoclast-like cells were formed in cocultures of a mouse marrow-derived stromal cell line (ST2) with mouse spleen cells in the presence of 1 alpha, 25-dihydroxyvitamin D3 and dexamethasone. In this study, we developed a new coculture system to determine the origin of osteoclasts. When relatively small numbers of mononuclear cells (10(3)-10(5) cells per well) obtained from mouse bone marrow, spleen, thymus, or peripheral blood were cultured for 12 days on the ST2 cell layers, they formed colonies with a linear relationship between the number of colonies formed and the number of hemopoietic cells inoculated. Tartrate-resistant acid phosphatase (TRAPase)-positive mononuclear and multinucleated cells appeared in the colonies (TRAPase-positive colonies) in response to 1 alpha, 25-dihydroxyvitamin D3 and dexamethasone. When hemopoietic cells suspended in a collagen-gel solution were cultured on the ST2 cell layers to prevent their movement, TRAPase-positive colonies were similarly formed, indicating that each colony originated from a single cell. All of the colonies consisted of nonspecific esterase-positive cells. The monocyte-depleted population prepared from peripheral blood failed to form colonies, whereas the monocyte-enriched population produced a large number of TRAPase-positive colonies. In addition, alveolar macrophages formed TRAPase-positive colonies most efficiently on the ST2 cell layers in the presence of the two hormones. Salmon 125I-labeled calcitonin specifically bound to the TRAPase-positive cells. Resorption lacunae were formed on dentine slices on which cocultures were performed. When direct contact between the peripheral blood cells and the ST2 cells was inhibited by a collagen-gel sheet, no TRAPase-positive cells were formed. These results indicate that osteoclasts are also derived from the mature monocytes and macrophages when a suitable microenvironment is provided by bone marrow-derived stromal cells.

Acid Phosphatase↗

PubMed1999

Mitogen-activated protein kinase phosphatase-1 (MKP-1) expression is induced by low oxygen conditions found in solid tumor microenvironments. A candidate MKP for the inactivation of hypoxia-inducible stress-activated protein kinase/c-Jun N-terminal protein kinase activity.

Pathophysiological hypoxia is an important modulator of gene expression in solid tumors and other pathologic conditions. We observed that transcriptional activation of the c-jun proto-oncogene in hypoxic tumor cells correlates with phosphorylation of the ATF2 transcription factor. This finding suggested that hypoxic signals transmitted to c-jun involve protein kinases that target AP-1 complexes (c-Jun and ATF2) that bind to its promoter region. Stress-inducible protein kinases capable of activating c-jun expression include stress-activated protein kinase/c-Jun N-terminal protein kinase (SAPK/JNK) and p38 members of the mitogen-activated protein kinase (MAPK) superfamily of signaling molecules. To investigate the potential role of MAPKs in the regulation of c-jun by tumor hypoxia, we focused on the activation SAPK/JNKs in SiHa human squamous carcinoma cells. Here, we describe the transient activation of SAPK/JNKs by tumor-like hypoxia, and the concurrent transcriptional activation of MKP-1, a stress-inducible member of the MAPK phosphatase (MKP) family of dual specificity protein-tyrosine phosphatases. MKP-1 antagonizes SAPK/JNK activation in response to diverse environmental stresses. Together, these findings identify MKP-1 as a hypoxia-responsive gene and suggest a critical role in the regulation of SAPK/JNK activity in the tumor microenvironment.

Activating Transcription Factor 2↗

PubMed1999

Position-specific gene expression in the liver lobule is directed by the microenvironment and not by the previous cell differentiation state.

Mechanisms directing position-specific liver gene regulation are incompletely understood. To establish whether this aspect of hepatic gene expression is an inveterate phenomenon, we used transplanted hepatocytes as reporters in dipeptidyl peptidase IV-deficient F344 rats. After integration in liver parenchyma, the position of transplanted cells was shifted from periportal to perivenous areas by targeted hepatic ablations with carbon tetrachloride. In controls, transplanted cells showed greater glucose-6-phosphatase and lesser glycogen content in periportal areas. This pattern was reversed when transplanted cells shifted from periportal to perivenous areas. Transplanted hepatocytes in perivenous areas exhibited inducible cytochrome P450 activity, which was deficient in periportal hepatocytes. Moreover, cytochrome P450 activity was rapidly extinguished in activated hepatocytes when these cells were transplanted into the nonpermissive liver of suckling rat pups. In cells isolated from the normal F344 rat liver, cytochrome P450 inducibility was originally greater in perivenous hepatocytes; however, periportal cells rapidly acquired this facility in culture conditions. These findings indicate that the liver microenvironment exerts supremacy over prior differentiation state of cells in directing position-specific gene expression. Therefore, persistence of specialized hepatocellular function will require interactions with regulatory signals and substrate availability, which bears upon further analysis of liver gene regulation, including in progenitor and/or stem cells.

Animals↗

PubMed2005

Characterization of the interaction between tumor necrosis factor-stimulated gene-6 and heparin: implications for the inhibition of plasmin in extracellular matrix microenvironments.

TSG-6, the secreted product of tumor necrosis factor-stimulated gene-6, is not constitutively expressed but is up-regulated in various cell-types during inflammatory and inflammation-like processes. The mature protein is comprised largely of contiguous Link and CUB modules, the former binding several matrix components such as hyaluronan (HA) and aggrecan. Here we show that this domain can also associate with the glycosaminoglycan heparin/heparan sulfate. Docking predictions and site-directed mutagenesis demonstrate that this occurs at a site distinct from the HA binding surface and is likely to involve extensive electrostatic contacts. Despite these glycosaminoglycans binding to non-overlapping sites on the Link module, the interaction of heparin can inhibit subsequent binding to HA, and it is possible that this occurs via an allosteric mechanism. We also show that heparin can modify another property of the Link module, i.e. its potentiation of the anti-plasmin activity of inter-alpha-inhibitor (IalphaI). Experiments using the purified components of IalphaI indicate that TSG-6 only binds to the bikunin chain and that this is at a site on the Link module that overlaps the HA binding surface. The association of heparin with the Link module significantly increases the anti-plasmin activity of the TSG-6.IalphaI complex. Changes in plasmin activity have been observed previously at sites of TSG-6 expression, and the results presented here suggest that TSG-6 is likely to contribute to matrix remodeling, at least in part, through down-regulation of the protease network, especially in locations containing heparin/heparan sulfate proteoglycans. The differential effects of HA and heparin on TSG-6 function provide a mechanism for its regulation and functional partitioning in particular tissue microenvironments.

Alpha-Globulins↗

PubMed2005

Shedding of collagen XVII ectodomain depends on plasma membrane microenvironment.

Collagen XVII, a hemidesmosomal component, mediates the adhesion of epidermal keratinocytes to the underlying basement membrane. It exists as a full-length transmembrane protein and a soluble ectodomain that is proteolytically released from the cell surface by sheddases of a disintegrin and metalloproteinase (ADAM) family; TACE, the tumor necrosis factor-alpha-converting enzyme, is the major physiological proteinase. Because both collagen XVII and the ADAMs are transmembrane proteins, their plasma membrane microenvironment can influence shedding. Lipid rafts, assemblies of sphingolipids and cholesterol within the plasma membrane, are responsible for the separation of membrane proteins and are thought to regulate shedding of cell surface proteins. In this study we analyzed the influence of the cholesterol-depleting agent methyl-beta-cyclodextrin (MbetaCD), which disintegrates lipid rafts, on the shedding of collagen XVII in HaCaT keratinocytes and in transfected COS-7 cells. Increasing concentrations of MbetaCD led to a dose-dependent decrease of membrane cholesterol levels and to stimulation of collagen XVII shedding. The stimulation was completely inhibited by sheddase inhibitors, and experiments with COS-7 cells co-transfected with TACE and collagen XVII demonstrated that TACE mediated the low cholesterol-dependent shedding. Co-patching analysis by double immunofluorescence staining revealed co-localization of collagen XVII with the raft resident phosphatidylinositol-linked placental alkaline phosphatase and segregation from the non-raft protein human transferrin receptor, indicating that a majority of collagen XVII molecules was incorporated into lipid rafts. These data deliver the first evidence for the role of plasma membrane lipid organization in the regulation of collagen XVII shedding and, therefore, in the regulation of keratinocyte migration and differentiation.

Animals↗

PubMed2003

The tumor microenvironment: a critical determinant of neoplastic evolution.

Evolution of neoplastic cells has generally been regarded as a cumulative intrinsic process resulting in altered cell characteristics enabling enhanced growth properties, evasion of apoptotic signals, unlimited replicative potential and gain of properties enabling the ability to thrive in ectopic tissues and in some cases, ability to metastasize. Recently however, the role of the neoplastic microenvironment has become appreciated largely due to the realization that tumors are not merely masses of neoplastic cells, but instead, are complex tissues composed of both a non-cellular (matrix proteins) and a cellular 'diploid' component (tumor-associated fibroblasts, capillary-associated cells and inflammatory cells), in addition to the ever-evolving neoplastic cells. With these realizations, it has become evident that early and persistent inflammatory responses observed in or around many solid tumors, play important roles in establishing an environment suitable for neoplastic progression by providing diverse factors that alter tissue homeostasis. Using cutaneous melanoma and squamous cell carcinoma as tumor models, we review the current literature focussing on inflammatory and tumor-associated fibroblast responses as critical mediators of neoplastic progression for these malignancies.

Animals↗

PubMed2005

The vulvar skin microenvironment: impact of tight-fitting underwear on microclimate, pH and microflora.

The aim of the present study was to investigate if tight-fitting underwear (string panties) equipped with string panty liners affected the vulvar skin microenvironment differently to regular panties with standard panty liners. Thirty-two healthy women participated in a crossover study where temperature, humidity, surface pH and aerobic microflora were measured on vulvar skin. Vulvar skin temperature was 35.2 +/- 0.19 (mean +/- SEM) and 35.3 +/- 0.17 degrees C, respectively, for the two underwear systems. Mean humidity and mean skin surface pH at vulvar skin did not differ between the two systems. Barely noticeable differences were found for the aerobic microflora both at labium majus and at perineum. The mean total number of microorganisms in the two different panty liners was the same, 6.0 +/- 0.15 and 6.0 +/- 0.16, respectively (log CFU per panty liner). The differences in panty and panty liner design studied seem to have negligible impact on the vulvar skin microclimate, skin surface pH and aerobic microflora. No support was found for the assumption that a string panty system would result in higher contamination of vulvar skin by anorectal microflora.

Adult↗

PubMed2006

The potential of the tumor microenvironment to influence Apo2L/TRAIL induced apoptosis.

Apo2L/TRAIL ligation of specific cell surface receptors (DR4 and DR5) induces apoptosis of many malignant cells with little effect on normal cells. This anti-tumor capability has been demonstrated using cell lines of many tumor types, both in vitro and in vivo when the cells are grown as xenografts. We have extended these studies to investigate the efficacy of Apo2L/TRAIL against patient tumor xenografts in SCID mice and found that the growth of many tumors, both of primary and metastatic origin, can be inhibited by Apo2L/TRAIL. The basis of resistance to Apo2L/TRAIL induced apoptosis in malignant cells and normal cells is not completely understood, but it is known that a variety of factors including hypoxia, MMPs and cytokines present in the tumor microenvironment can influence the response of malignant cells to Apo2L/TRAIL. Currently, the clinical potential of several molecules targeting the Apo2L/TRAIL receptors DR4 and DR5 is being investigated. Our goal in this review is to provide a brief overview of a number of factors that have potential to influence the response of patient tumors to Apo2L/TRAIL.

Animals↗

PubMed2006

Modulation of immune response by B7 family molecules in tumor microenvironments.

The importance of co-stimulatory and co-inhibitory molecules has been confirmed on a grand scale; with the identification of new B7 family molecules, possessing both immune activating and inhibiting functions, this family has exploded onto the scene of immune regulation. Nowhere, however, has the role of B7 family members been more apparent than in the fight against cancer. In this review, we will discuss recent data regarding the essential and complex role of B7 family members in regulating the immune response within tumor microenvironment.

Animals↗

PubMed1986

The in vitro sensitivities to radiation and misonidazole of mouse bone marrow cells derived from different microenvironments.

Previous studies had indicated that haematopoietic cells (CFU-GM) which reside within compact bone are resistant to ionizing radiation and sensitive to the cytotoxic action of misonidazole (MISO) relative to cells which reside within the core of mouse femurs. It was postulated that the microenvironment within compact bone might be relatively hypoxic. CFU-GM from femur cores (Fraction 1) and from compact bone (Fraction 3) have been exposed to ionizing radiation and to the hypoxic cell radiosensitizer, MISO, under controlled conditions of oxygenation in vitro. The inherent radiosensitivity of aerated Fraction 1 CFU-GM is similar to their in vivo radiosensitivity. An oxygen enhancement ratio of 2.2 is observed for these cells in vitro. On the other hand, the in vitro radiosensitivity of hypoxic Fraction 3 CFU-GM was similar to their in vivo radiosensitivity. The oxygen enhancement ratio for Fraction 3 cells was 1.5, significantly lower than that observed for Fraction 1 cells. When CFU-GM cells were exposed to MISO under hypoxic conditions in vitro it was found that Fraction 3 CFU-GM were more sensitive to its cytotoxic action than were cells from Fraction 1. These data are consistent with the interpretation that some CFU-GM reside in an environment of relative hypoxia within the compact bone of the mouse femur.

Animals↗

PubMed2005

Acute myelogenous leukemia--microenvironment interactions: role of endothelial cells and proteasome inhibition.

How leukemia progenitors interact with marrow microenvironment components is poorly understood. In this work, the effects of endothelial coculture on acute myelogenous leukemia (AML) blast survival is examined as are the effects of endothelial coculture on the impact of a cytotoxic agent such as cytarabine. Similar to marrow stromal cells, endothelial cells are able to increase survival and proliferation of AML blasts and to partially protect against cytarabine effects. The proteasome inhibitor, bortezomib, has inhibitory effects in multiple myeloma in part through effects on marrow stromal cells. Bortezomib has been found to inhibit AML blast survival. Such inhibition is less, however, in the presence of endothelial monolayers. Furthermore, AML blast transmigration through human umbilical vein endothelial cells is inhibited by bortezomib. These studies demonstrate that AML is subject to influence of endothelial cells and of agents such as bortezomib which have potential impact on AML interaction with the microenvironmental niche.

Apoptosis↗

PubMed1999

The Hematopoietic Microenvironment: Stromal Cell Types: Characterization and Function In Situ and In Vitro.

The murine hematopoietic stroma is essential for the homing and the continued replication of hematopoietic stem cells following transplantation and appears to control their lineage proliferation. In our studies it has been found to consist of 3 cell types with differing antigenic displays, growth factor responses and interactions when placed in culture. These characteristics are in keeping with their classifications as myofibroblasts, endothelial like cells and macrophages, respectively. Cell adhesion molecules (CAMs) and early acting cytokines have been found to be associated with these cell types. Only the myofibroblast type has been found to support proliferation of the descendants of long term repopulating stem cells (LTRC) plated over their confluent layer. The endothelial like cell type, and possibly the macrophage, were found to suppress not only the growth of LTRC but, also, that of the myofibroblasts obtained from the same marrow samples. Culture medium obtained from near-confluent growth of the endothelial like cells contained a growth inhibiting molecule of less than 3000 da. capable of inhibiting cells of several types, including the stromal myofibroblasts. The endothelial like cells were shown to unilaterally express VCAM-1 in culture, as well as vWf and endothelial cell specific antigens. Tissue sections of femurs from normal irradiated recipients taken 1 hour post-transplantation revealed Lac-Z marked donor stem cells lodged just external to the endothelial lining of thin walled vessels and in contact with myofibroblasts. Previous studies had shown that some stem cells enter replication at these sites within 48 hours of lodgment. It is suggested that a balance of growth stimulation versus suppression may be maintained between the myofibroblasts and the endothelial like cell types, respectively, in the functioning marrow stroma. Both the myofibroblastoid and the endothelial like stromal cells of old mice displayed a reduced replicative rate in vivo and a reduced replicative capacity in vitro. This suggests that treatments that induce damage to the marrow microenvironment may be especially destructive in aged individuals. In recent experiments it has become clear that the stromal cell population that includes cells identifiable as alkaline phosphatase positive myofibroblasts also contains cells that produce osteocalcin, osteonectin and bone sialoprotein, and deposit von Kossa positive calcium. Whether this results from a single cell lineage or two lineages of similar morphology and alkaline phosphatase expression is under investigation.

Journal Article↗

PubMedDate not supplied

The microenvironment of AFT024 cells maintains primitive human hematopoiesis by counteracting contact mediated inhibition of proliferation.

We have previously shown that maintenance of primitive human hematopoietic stem cells is poor when cultured in contact with marrow stromal feeders. However, when separated from stromal contact, human progenitors can be maintained because adhesion mediated proliferation inhibition does not occur. In this study we demonstrate how the murine fetal liver cell line, AFT024, supports primitive human hematopoiesis better in contact cultures compared to primary feeders. We evaluated if better progenitor maintenance in contact with AFT024 cells can be explained by decreased adhesion itself or decreased adhesion mediated inhibition of proliferation. We show that primitive human hematopoietic cells adhered equally well to AFT024 and primary feeders, such as M2-10B4. Further, contact with metabolically inactive AFT024 cells prevented cell cycle progression and decreased maintenance of primitive progenitors to the same extent as contact with M2-10B4 feeders. However, contact with viable AFT024 feeders did not inhibit proliferation, suggesting that AFT024-factors counteract contact mediated inhibition of proliferation. Cytokine production by M2-10B4 and AFT024 cells was similar. Large-size O-sulfated heparan sulfate glycosaminoglycans, known to be important for hematopoietic support, were found only in AFT024-matrix. We hypothesize that these factors may explain, in part, our observations. Finally, we show that more than 100% of primitive myeloid progenitors could be maintained for at least five weeks when cultured in contact with AFT024 feeders in the presence of Interleukin-3 and Macrophage Inflammatory Protein-1alpha. In conclusion, AFT024 cells produce factor(s), that counteract contact induced growth inhibition of primitive human hematopoietic progenitors, leading to expansion of these cells in contact with the microenvironment.

Animals↗

PubMed2004

Myotubes differentiate optimally on substrates with tissue-like stiffness: pathological implications for soft or stiff microenvironments.

Contractile myocytes provide a test of the hypothesis that cells sense their mechanical as well as molecular microenvironment, altering expression, organization, and/or morphology accordingly. Here, myoblasts were cultured on collagen strips attached to glass or polymer gels of varied elasticity. Subsequent fusion into myotubes occurs independent of substrate flexibility. However, myosin/actin striations emerge later only on gels with stiffness typical of normal muscle (passive Young's modulus, E approximately 12 kPa). On glass and much softer or stiffer gels, including gels emulating stiff dystrophic muscle, cells do not striate. In addition, myotubes grown on top of a compliant bottom layer of glass-attached myotubes (but not softer fibroblasts) will striate, whereas the bottom cells will only assemble stress fibers and vinculin-rich adhesions. Unlike sarcomere formation, adhesion strength increases monotonically versus substrate stiffness with strongest adhesion on glass. These findings have major implications for in vivo introduction of stem cells into diseased or damaged striated muscle of altered mechanical composition.

Acrylic Resins↗