The sulfation of biomimetic glycosaminoglycan substrates controls binding of growth factors and subsequent neural and glial cell growth

Malaeb, Waddah; Bahmad, Hisham F.; Abou-Kheir, Wassim; Mhanna, Rami

doi:10.1039/c9bm00964g

Cited by 22 publications

(25 citation statements)

References 76 publications

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“…We and others have shown earlier that increasing the sulfation of biomimetic sulfated GAGs enhances the growth of chondrocytes [36,59], neural cell lines [43], and fibroblasts [60], which is in contradiction with the finding of the current study that showed a decrease in cell growth. The discrepancy in results between the current study and the previous ones can be explained by the fact that previous studies used sulfated polysaccharides stabilized to a substrate whether in 2D or 3D unlike the current study where AlgSulf n were added in solution [36,43]. Sulfated polysaccharides used in previous studies were sterically less mobile while in the current study they might encapsulate growth factors, making them unavailable for GF receptors on the cell surface.…”

Section: Discussioncontrasting

confidence: 99%

“…GF binding is critical for multiple cellular events, including proliferation, differentiation, and migration. This makes sulfation pivotal for normal cell growth, for example in wound healing and regeneration, but also for cancer cell growth and metastasis [29,36,43]. Biomimetic sulfated GAGs also showed proliferative effects on normal chondrocytes [36] and neural cell lines [43] possibly through increased GF binding.…”

Section: Discussionmentioning

confidence: 99%

“…This makes sulfation pivotal for normal cell growth, for example in wound healing and regeneration, but also for cancer cell growth and metastasis [29,36,43]. Biomimetic sulfated GAGs also showed proliferative effects on normal chondrocytes [36] and neural cell lines [43] possibly through increased GF binding. It is worth noting that our current and previous studies [36,43] assessed the role of the average DS of AlgSulf n treatment groups, which comprise a heterogeneous mixture of chains with a distribution of molecular weights, DSs, and positions of sulfate moieties (regioselectivity) that might have different individual contributions to cell behavior.…”

Section: Discussionmentioning

confidence: 99%

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Anti-Tumor Effects of Biomimetic Sulfated Glycosaminoglycans on Lung Adenocarcinoma Cells in 2D and 3D In Vitro Models

et al. 2020

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Lung cancer development relies on cell proliferation and migration, which in turn requires interaction with extracellular matrix (ECM) components such as glycosaminoglycans (GAGs). The mechanisms through which GAGs regulate cancer cell functions are not fully understood but they are, in part, mediated by controlled interactions with cytokines and growth factors (GFs). In order to mechanistically understand the effect of the degree of sulfation (DS) of GAGs on lung adenocarcinoma (LUAD) cells, we synthesized sulfated alginate (AlgSulf) as sulfated GAG mimics with DS = 0.0, 0.8, 2.0, and 2.7. Human (H1792) and mouse (MDA-F471) LUAD cell lines were treated with AlgSulf of various DSs at two concentrations 10 and 100 µg/mL and their anti-tumor properties were assessed using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), trypan blue exclusion, and wound healing assays for 2D models and sphere formation assay for the 3D model. The proliferation and number of live MDA-F471 cells at the concentration of 100 µg/mL decreased significantly with the increase in the DS of biomimetic GAGs. In addition, the increase in the DS of biomimetic GAGs decreased cell migration (p < 0.001 for DS = 2.0 and 2.7 compared to control) and decreased the diameter and number of spheres formed (p < 0.001). The increased DS of biomimetic GAGs attenuated the expression of cancer stem cell (CSC)/progenitor markers in the 3D cultures. In conclusion, GAG-mimetic AlgSulf with increased DS exhibit enhanced anti-proliferative and migratory properties while also reducing growth of KRAS-mutant LUAD spheres in vitro. We suggest that these anti-tumor effects by GAG-mimetic AlgSulf are possibly due to differential binding to GFs and consequential decreased cell stemness. AlgSulf may be suitable for applications in cancer therapy after further in vivo validation.

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Section: Discussioncontrasting

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Anti-Tumor Effects of Biomimetic Sulfated Glycosaminoglycans on Lung Adenocarcinoma Cells in 2D and 3D In Vitro Models

et al. 2020

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“…Here, sAlg with DS = 1.0 showed a higher degree of interaction with FGF‐2 compared with DS = 1.4, attributed to a higher relative chain flexibility. [ 271 ] This was not observed for interaction studies of sAlg in solution or in layer‐by‐layer films, where a similarly high DS resulted in the highest degree of FGF‐2 binding. [ 272 ] Recently, release of growth factors from nanofibrous and printed structures based on sAlg has been investigated.…”

Section: Biological Properties and Biomedical Applications Of Espsmentioning

confidence: 99%

Engineered Sulfated Polysaccharides for Biomedical Applications

Arlov

Rütsche

Korayem

et al. 2021

Adv Funct Materials

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Sulfated polysaccharides are ubiquitous in living systems and have central roles in biological functions such as organism development, cell proliferation and differentiation, cellular communication, tissue homeostasis, and host defense. Engineered sulfated polysaccharides (ESPs) are structural derivatives not found in nature but generated through chemical and enzymatic modification of natural polysaccharides, as well as chemically synthesized oligo‐ and polysaccharides. ESPs exhibit novel and augmented biological properties compared with their unmodified counterparts, mainly through facilitating interactions with other macromolecules. These interactions are closely linked to their sulfation patterns and backbone structures, providing a means to fine‐tune biological properties and characterize structural–functional relationships by employing well‐characterized polysaccharides and strategies for regioselective modification. The following review provides a comprehensive overview of the synthesis and characterization of ESPs and of their biological properties. Through the pioneering research presented here, key emerging application areas for ESPs, which can lead to novel breakthroughs in biomedical research and clinical treatments, are highlighted.

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“…Chemoattractants, such as growth factors and chemokines, play crucial roles in situ cell recruitment (Zhang et al, 2020). They can be delivered into local defect areas by being simply injected alone or loaded within scaffold matrix (Chuma et al, 2004;Malaeb et al, 2019). However, the use of these bioactive factors may result in some undesirable side-effects (van Beuningen et al, 2000;Miller et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

Simultaneous Recruitment of Stem Cells and Chondrocytes Induced by a Functionalized Self-Assembling Peptide Hydrogel Improves Endogenous Cartilage Regeneration

Sun²,

et al. 2020

Front. Cell Dev. Biol.

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The sulfation of biomimetic glycosaminoglycan substrates controls binding of growth factors and subsequent neural and glial cell growth

Abstract: This work shows that alginates can be sulfated to engineer defined substrates that control growth factor binding and neural growth.

Cited by 22 publications

References 76 publications

Anti-Tumor Effects of Biomimetic Sulfated Glycosaminoglycans on Lung Adenocarcinoma Cells in 2D and 3D In Vitro Models

Anti-Tumor Effects of Biomimetic Sulfated Glycosaminoglycans on Lung Adenocarcinoma Cells in 2D and 3D In Vitro Models

Engineered Sulfated Polysaccharides for Biomedical Applications

Simultaneous Recruitment of Stem Cells and Chondrocytes Induced by a Functionalized Self-Assembling Peptide Hydrogel Improves Endogenous Cartilage Regeneration

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