bims-supasi 2025-09-21 papers

bims-supasi

Biomed News

on Sulfation pathways and signalling

Issue of 2025–09–21
eleven papers selected by
Jonathan Wolf Mueller, University of Birmingham

Nanoscopy Reveals Heparan Sulfate Clusters as Docking Sites for SARS-CoV-2 Attachment and Entry.
Low-molecular-weight dextran sulfate sodium as novel heparanase inhibitor preventing breast cancer metastasis in mice by inhibiting migration and angiogenesis.
De Novo Chemoenzymatic Assembly of Complex Sulfated N-Glycans to Comprehensively Profile the Ligand Binding of Human Siglecs.
Insights into the renal protective effects of 7-phenylheptanoic acid in chronic kidney disease mice: Modulation of indoxyl sulfate production and gut microbiome homeostasis.
Optimized 3'-Phosphoadenosine-5'-phosphosulfate Biosynthesis via Yeast-Powered ATP Regeneration and Biotin-Streptavidin Enzyme Immobilization.
Cardiometabolic outcomes in girls with premature adrenarche: a longitudinal analysis of typical vs. exaggerated presentations.
Exploring the role of structural and dynamic complexity in SARS-CoV-2 Nucleocapsid protein-heparin interactions by NMR.
A Novel Cholesterol-Reducing Mechanism of Polygonati Rhizoma: Dual Action via Bacteroides-Mediated Cholesterol Sulfonation and Feedback Inhibition of ACAT2 by Sulfated Metabolite.
The complete λ-carrageenan depolymerization cascade from a marine Pseudoalteromonad revealed by structural analysis of the enzymes.
Gut-microbiota-derived indole sulfate promotes heart failure in chronic kidney disease.
Sulphated polysaccharides and biomaterials: Steering stem cell fate.

bioRxiv. 2025 Sep 09. pii: 2025.09.08.674976. [Epub ahead of print]

Nanoscopy Reveals Heparan Sulfate Clusters as Docking Sites for SARS-CoV-2 Attachment and Entry.

Sue Han, Xin Wang, Tiansheng Li, Ammar Mohseni, Ivan Kosik, Chung Yu Chan, Alberto Domingo López-Muñoz, Jessica Matthias, Reid Suddaby, Zhixiong Wang, Albert J Jin, Christian A Wurm, Jonathan W Yewdell, Ling-Gang Wu.

Virus entry is thought to involve binding a unique receptor for cell attachment and cytosolic entry. For SARS-CoV-2 underlying the COVID-19 pandemic, angiotensin- converting enzyme 2 (ACE2) is widely assumed as the receptor. Using advanced light microscopy to resolve individual virions and receptors, we found instead that heparan sulfate (HS), not ACE2, mediates SARS-CoV-2 cell-surface attachment and subsequent endocytosis. ACE2 functions only downstream of HS to enable viral genome expression. Instead of binding single HS molecules that electrostatically interact with viral surface proteins weakly, SARS-CoV-2 binds clusters of ∼6-137 HS molecules projecting 60-410 nm above the plasma membrane. These tall, HS-rich clusters, present at about one per 6 μm², act as docking sites for viral attachment. Blocking HS binding with the clinically used HS- binding agent pixantrone strongly inhibited the clinically relevant SARS-CoV-2 Omicron JN.1 subvariant from attaching to and infecting human airway cells. This work establishes a revised entry paradigm in which HS clusters mediate SARS-CoV-2 attachment and endocytosis, with ACE2 acting downstream, thereby identifying HS interactions as a key anti-COVID-19 strategy. This paradigm and its therapeutic implications may apply broadly beyond COVID-19 because, analogous to SARS-CoV-2, HS binds many other viruses but is only considered an attachment regulator.
Statement of Significance: Viral entry, a crucial antiviral target, is typically thought to involve binding its unique receptor for the cell surface attachment and subsequent entry. We examined this concept with advanced microscopies to resolve individual receptors and SARS-CoV-2 virions responsible for the COVID-19 pandemic. We discovered two receptors for viral entry: heparan sulfate, a polysaccharide that may bind many viruses, mediates viral attachment and subsequent endocytosis, whereas angiotensin-converting enzyme 2 (ACE2), the generally assumed SARS-CoV-2 receptor, acts only downstream to facilitate viral infection. This new model suggests perturbation of HS binding as a more effective anti-COVID-19 strategy than previously recognized. It may apply broadly beyond COVID-19 because, analogous to SARS-CoV-2, HS binds many other viruses but is only considered an attachment regulator.

DOI: https://doi.org/10.1101/2025.09.08.674976
Carbohydr Polym. 2025 Dec 01. pii: S0144-8617(25)01040-9. [Epub ahead of print]369 124255

Low-molecular-weight dextran sulfate sodium as novel heparanase inhibitor preventing breast cancer metastasis in mice by inhibiting migration and angiogenesis.

Yidian Mo, Guohao Song, Linbo Fu, Yuchao Wang, Tongtong Geng, Ao Sun, Baodi Gou, Xiangbao Meng, Liangren Zhang, Heng Wang, Zhongjun Li, Zhongtang Li.

  The invasion and metastasis of aggressive breast malignancies are the main reasons of poor prognosis due to the lack of effective treatment. Heparanase (HPSE) can promote the migration and angiogenesis of breast cancer by degrading heparan sulfate (HS), indicating HPSE as an attractive target for anti-metastasis. Herein, we developed low-molecular-weight dextran sulfate sodium (LMW-DSS), a sulfated polysaccharide semi-synthesized from dextran, serving as an HS mimic thereby acting as a potent HPSE inhibitor. In vitro study showed that LMW-DSS exerted its effects through direct binding to HPSE, leading to both significant inhibition of HPSE activity and down-regulation of its expression. Moreover, the inhibition of HPSE reduced the migration and invasion of 4 T1 mammary carcinoma cells while suppressing the associated epithelial-mesenchymal transition (EMT). LMW-DSS also suppressed angiogenesis of human umbilical vein endothelial cells (HUVECs) with inhibitory effects on proangiogenic factors. Importantly, we confirmed the therapeutic anti-metastatic efficacy of LMW-DSS in suppressing pulmonary metastasis within 4 T1-Luc metastatic mouse model, alongside its in vivo safety profile. Given its minimal bleeding risk, LMW-DSS presents a promising and reliable therapeutic approach for combating aggressive breast malignancies.

Keywords:  Anti-angiogenesis; Anti-metastasis; Dextran sulfate sodium; Heparanase; Mammary carcinoma cells

DOI:  https://doi.org/10.1016/j.carbpol.2025.124255
J Am Chem Soc. 2025 Sep 15.

De Novo Chemoenzymatic Assembly of Complex Sulfated N-Glycans to Comprehensively Profile the Ligand Binding of Human Siglecs.

Shengzhou Ma, Jiabin Zhang, Fangyu Wei, Xiao Tian, Yinping Tian, Liuqing Wen.

The Siglec family represents one of the major classes of human glycan-binding proteins (GBPs) that regulates a broad range of biological processes through engagement with their glycan ligands. Human Siglecs have attracted a great deal of attention in recent years, as they are regarded as new immune checkpoints. The disruption of Siglec-sialoglycan interactions represents a promising next-generation strategy for cancer immunotherapy. In addition to the sialic acid moiety, it has been well established that glycan sulfation plays an essential role in the ligand binding of human Siglecs. Therefore, there is an urgent need to thoroughly understand the subtle differences in the glycan scaffolds and sulfation patterns that govern Siglec binding. N-Glycans are the most abundant class of glycans occurring in living cells, while sulfation is the most widespread postglycosylation modification of N-glycans, indicating that sulfated N-glycans serve as key ligands for human Siglecs. However, the synthetic generation of large libraries of complex sulfated N-glycans is impractical as sulfation introduces additional challenges to the already demanding process of N-glycan synthesis. Herein, we describe a de novo chemoenzymatic approach for the efficient preparation of complex sulfated N-glycans. Using this approach, a comprehensive 72-member library of sulfated N-glycans encompassing the most typical complex structures was successfully prepared. With the well-defined library (comprising 72 sulfated N-glycans and 26 nonsulfated controls), we systematically investigated the binding activities of all human Siglecs. Beyond the synthetic breakthroughs, this work provides the most comprehensive profile to date for understanding how sulfation patterns and N-glycan scaffolds affect Siglec ligand binding, which will have an immediate impact on the development of Siglec-targeted immunotherapy strategies.

DOI: https://doi.org/10.1021/jacs.5c11949
Drug Metab Dispos. 2025 Aug 22. pii: S0090-9556(25)09158-5. [Epub ahead of print]53(10): 100149

Insights into the renal protective effects of 7-phenylheptanoic acid in chronic kidney disease mice: Modulation of indoxyl sulfate production and gut microbiome homeostasis.

Masahiro Tokuno, Kindness Lomotey Commey, Asami Yamamoto, Maho Tokushige, Kenji Tsukigawa, Koji Nishi, Masaki Otagiri, Keisuke Ekino, Keishi Yamasaki.

  7-Phenylheptanoic acid (7-PH) has been reported to slow the progression of chronic kidney disease (CKD) in mice. Although the mechanism behind this renal protection remains unclear, it is strongly linked to reduced production of indoxyl sulfate (IS), a uremic toxin derived from dietary L-tryptophan through a multistep enzymatic process. It is also known that there is a strong association between CKD progression and gut microbiome dysbiosis. This study aimed to determine the involvement of each enzymatic step and identify the primary target enzymes through which 7-PH suppresses IS production, as well as investigate whether the protective effects of 7-PH involve microbiome modulation. First, we evaluated the effects of 7-PH on tryptophan indole-lyase (TIL), cytochrome P450 2E1 (CYP2E1), and sulfotransferase enzymes using in vitro enzyme kinetic studies. We then analyzed the impact of 7-PH on gut microbiome homeostasis in adenine-induced CKD mice using high-throughput 16S rRNA gene sequencing of fecal samples. Our findings indicate that 7-PH primarily targets the conversion of L-tryptophan to indole by acting as a competitive inhibitor of TIL (Ki = 92 μM). It also exhibits weak noncompetitive inhibition of CYP2E1 but does not affect sulfotransferase activity. Microbiome analysis revealed that 7-PH attenuates CKD-associated gut microbiota dysbiosis by selectively preserving beneficial bacterial taxa, such as Muribaculaceae and Alloprevotella, while inhibiting dysbiotic and opportunistic pathogenic groups, including Staphylococcus and Oligella. Therefore, the renal protective effects of 7-PH involve at least 2 interconnected mechanisms: the suppression of IS production through TIL inhibition and the modulation of the gut microbiome. SIGNIFICANCE STATEMENT: The mechanisms behind the renal protective effects of 7-phenylheptanoic acid (7-PH) in chronic kidney disease mice have been clarified. 7-PH reduces indoxyl sulfate production by primarily inhibiting tryptophan indole-lyase activity. Additionally, 7-PH modulates the gut microbiome by preserving beneficial bacterial taxa while selectively suppressing opportunistic pathogens, thereby attenuating chronic kidney disease-associated microbiome dysbiosis.

Keywords:  16S rRNA sequencing; 7-Phenylheptanoic acid; Fecal microbiota; Indoxyl sulfate roduction; Inhibition; Tryptophan indole-lyase

DOI:  https://doi.org/10.1016/j.dmd.2025.100149
Biochemistry. 2025 Sep 18.

Optimized 3'-Phosphoadenosine-5'-phosphosulfate Biosynthesis via Yeast-Powered ATP Regeneration and Biotin-Streptavidin Enzyme Immobilization.

Xin-Yu Li, Jian-Qun Deng, Yu-Han Zhao, Ya-Lin Cao, Yi Li, Jin Hou, Xue-Ping Guo, Ju-Zheng Sheng.

3'-Phosphoadenosine-5'-phosphosulfate (PAPS), a universal sulfate donor for sulfation reactions, is indispensable for synthesizing bioactive molecules including therapeutic glycosaminoglycans and sulfolipids; however, its enzymatic production on an industrial scale is constrained by ATP overconsumption and the limited free enzyme reusability. We report an integrated biocatalytic platform combining ATP regeneration with affinity immobilization to enable sustainable PAPS biosynthesis. A polyphosphate kinase-driven ATP regeneration system achieved 86% PAPS conversion efficiency by regenerating ADP using low-cost polyphosphate. Biotin-streptavidin affinity immobilization enhanced operational stability, retaining >50% activity over six reuse cycles with a cumulative PAPS titer of 12.02 g/L. Coupling adenosine-converting Saccharomyces cerevisiae whole-cell catalysts with this system decreased substrate costs by 80.7% and delivered 96% molar PAPS yield from adenosine. This work provides a sustainable platform for industrial PAPS biosynthesis to promote sulfated biomolecule production, including glycosaminoglycans and other therapeutics.

DOI: https://doi.org/10.1021/acs.biochem.5c00373
J Pediatr Endocrinol Metab. 2025 Sep 15.

Cardiometabolic outcomes in girls with premature adrenarche: a longitudinal analysis of typical vs. exaggerated presentations.

Gülcan Seymen, Murat İmal, Şükrü Hatun.

   OBJECTIVES: To evaluate cardiometabolic risk factors in girls with premature adrenarche (PA), with a specific focus on outcomes based on adrenal androgen levels (typical vs. exaggerated adrenarche).
METHODS: Eighty-four girls with PA were followed from diagnosis to mid-puberty. Clinical, biochemical, and hormonal parameters were assessed at both time points. Participants were stratified based on dehydroepiandrosterone sulfate (DHEAS) levels: typical PA (40-130 μg/dL) and exaggerated adrenarche (>130 μg/dL). Age- and sex-matched controls (n=58) were included for pubertal comparisons.
RESULTS: At baseline, 25 % of PA girls were overweight/obese, and 22 % had elevated HOMA-IR. Exaggerated adrenarche was present in 19 % of subjects. By puberty, overweight/obesity prevalence rose to 33.3 %, with significant increases in fasting insulin, HOMA-IR, and declines in insulin sensitivity indices (QUICKI, FGIR). Comparisons with controls revealed significantly higher BMI, waist circumference, and insulin resistance among PA girls. However, there were no significant metabolic differences between exaggerated and typical PA groups, except for a higher waist circumference in the exaggerated group.
CONCLUSIONS: Elevated mid-childhood DHEAS does not independently predict worsened metabolic outcomes by puberty. Baseline adiposity, not androgen level, is the principal determinant of insulin resistance and cardiometabolic risk in PA. Lifestyle interventions targeting weight management are crucial in mitigating future risk.

Keywords:  DHEAS; adolescence; cardiometabolic risk; insulin resistance; obesity; premature adrenarche

DOI:  https://doi.org/10.1515/jpem-2025-0232
J Mol Biol. 2025 Sep 11. pii: S0022-2836(25)00503-0. [Epub ahead of print] 169437

Exploring the role of structural and dynamic complexity in SARS-CoV-2 Nucleocapsid protein-heparin interactions by NMR.

Tessa Bolognesi, Marco Schiavina, Cristina Ciabini, Michela Parafioriti, Cristina Gardini, Stefano Elli, Marco Guerrini, Roberta Pierattelli, Isabella C Felli.

  Among the structural proteins of SARS-CoV-2, the nucleocapsid (N) protein stands out for its pronounced structural heterogeneity and multifunctionality throughout the viral life cycle. Recent studies have demonstrated that the N protein localizes to the surface of infected and neighbouring non-infected cells, by interacting with heparan sulfate in the extracellular matrix. The N protein (419 residues) comprises two folded domains (44NTD180 and 249CTD361) interspersed with three intrinsically disordered regions (1IDR143, 181IDR2248, 362IDR3419). The coexistence of ordered and disordered elements raises a key question: how does this structural heterogeneity influence N's interactions with biological partners? Here we employ high-resolution NMR spectroscopy as the primary technique to characterize the interaction of three N protein constructs (44NTD180, 1NTR248, and 1N419) with heparin-based ligands of increasing complexity. NMR provides atomic level information on the structured NTD domain and on the otherwise difficult to investigate flexible regions. Molecular dynamics simulations further probe the interaction between NTD and short heparin oligosaccharides. Our data reveal a clear correlation between ligand size and binding affinity: longer saccharide chains promote stronger binding. Additionally, the inclusion of intrinsically disordered regions in the NTR construct significantly enhances the interaction compared to NTD, highlighting the functional relevance of structural disorder. Finally, the full-length protein exhibits distinct spectral behaviour with the investigated heparin-based ligands, potentially reflecting additional binding contributions and altered dynamics arising from its complex structure. These findings underscore the utility of NMR spectroscopy in elucidating the dynamic, multivalent nature of protein-polyanion interactions, particularly in highly flexible proteins with a modular domain organization.

Keywords:  Heparin; Molecular dynamics simulation; Multidomain protein; Nuclear Magnetic Resonance; SARS-CoV-2

DOI:  https://doi.org/10.1016/j.jmb.2025.169437
J Ethnopharmacol. 2025 Sep 17. pii: S0378-8741(25)01311-X. [Epub ahead of print] 120619

A Novel Cholesterol-Reducing Mechanism of Polygonati Rhizoma: Dual Action via Bacteroides-Mediated Cholesterol Sulfonation and Feedback Inhibition of ACAT2 by Sulfated Metabolite.

Xinhong Wang, Manru Chen, Yu Su, Xia Zhang, Jingzhi Chen, Ziwei Huang, Jianhui Xie, Qingfeng Xie, Lianfang He, Lingye Su, Ziren Su, Hongfeng Wang, Yucui Li.

   ETHNOPHARMACOLOGICAL RELEVANCE: Polygonati Rhizoma (PR) has the function of "invigorating spleen and tonifying kidney", and is historically applied as a homology of medicine and food to prevent and treat dyslipidemia in China. However, there is limited experimental evidence to buttress this application, and the underlying mechanism has not been fully deciphered.
AIM OF THE STUDY: To analyze the composition and illuminate the cholesterol-lowering potential and molecular mechanism of PR's aqueous extract (PRE) in high-fat emulsion (HFE)-induced hypercholesterolemia mouse model.
MATERIALS AND METHODS: Ion chromatograph was employed to determine the monosaccharide composition of PRE. HFE-induced Kunming mouse model was constructed to unravel the anti-hypercholesterolemia effect of PRE. Metagenomic sequences and liquid chromatography-mass spectrometry (LC-MS) analysis were performed to elucidate the mechanism through which PR regulated cholesterol metabolism. Antibiotic cocktail (ABX) intervention and fecal microbiota transplantation (FMT) were used to validate whether PRE regulated cholesterol metabolism through the intestinal microbiota. The cholesterol-reducing effect of cholesterol sulfate (CS) was explored in poloxamer 407 (P407)-induced mouse model of dyslipidemia. Molecular docking and molecular dynamics (MD) simulation were also employed to elucidate the underlying mechanisms. Furthermore, a combination of qRT-PCR, Western blot, and surface plasmon resonance (SPR) were employed to delineate its mechanism.
RESULTS: Our study indicated that the polysaccharides of PRE were mainly composed of fructose (92.33%) and glucose (5.25%). PRE treatment effectively blocked body weight gain, significantly decreased serum and hepatic levels of triglycerides (TG), total cholesterol (TC), and low-density lipoprotein cholesterol (LDL-C), and increased high-density lipoprotein cholesterol (HDL-C) level. Additionally, PRE ameliorated hepatic lipid accumulation in mice with HFE-elicited hypercholesterolemia. Notably, metagenomic sequencing and LC-MS analysis indicated that PRE markedly increased the abundance of intestinal genera Bacteroides and significantly elevated the fecal CS concentration in HFE mice. Genome-based functional analysis further indicated that cofactors of sulfonation (ATP sulfurylase CysD and CysN, BT0414-BT0415) were significantly upregulated after treatment with PRE. The cholesterol-lowering effect of PRE was largely contingent upon microbial conversion of cholesterol-to-CS mediated by Bacteroides, as validated by antibiotics-induced intestinal microbiota depletion in pseudo-germ-free model and restoration of gut microbiota through FMT. In vitro study also showed that PRE promoted the growth of Bacteroides thetaiotaomicron. Furthermore, CS markedly alleviated serum, hepatic, bile, and fecal levels of TG, TC, LDL-C, HDL-C and TBA, indicative of appreciable lipid-lowering effect. MD simulation and SPR result indicated that CS directly bound to ACAT2. Consistent with this interaction, CS greatly downregulated the mRNA and protein expression of ACAT2 in small intestinal tissue.
CONCLUSION: These findings for the first time suggested that PR acted as a prebiotic agent to ameliorate hypercholesterolemia, at least in part, via dual mechanism involving modulation of Bacteroides-mediated sulfonation metabolic pathway and feedback inhibition of ACAT2 by CS, highlighting its therapeutic potential for cholesterol-related disorders. This work might also offer novel mechanistic insight and further buttressed the ethnopharmacological application of PR in the therapy of hypercholesterolemia.

Keywords:  ACAT2; Bacteroides; Polygonati Rhizoma; cholesterol sulfation; gut microbiota; hypercholesterolemia

DOI:  https://doi.org/10.1016/j.jep.2025.120619
J Biol Chem. 2025 Sep 15. pii: S0021-9258(25)02571-2. [Epub ahead of print] 110719

The complete λ-carrageenan depolymerization cascade from a marine Pseudoalteromonad revealed by structural analysis of the enzymes.

Chelsea J Vickers, Andrew G Hettle, Joanne K Hobbs, Sarah Shapiro-Ward, Benjamin Pluvinage, Brendon J Medley, Bailey E McGuire, Liam Mihalynuk, Nitin Nitin, Wesley F Zandberg, Alisdair B Boraston.

  Carrageenans are a complex group of polysaccharides derived from the cell walls of red macroalgae. They are an abundant, yet recalcitrant nutrient source for most marine heterotrophic bacteria. Some member species of the Pseudoalteromonas genus are effective at metabolizing carrageenan. However, the enzymatic pathway for λ-carrageenan, one of the most sulfated naturally occurring polysaccharides, remains unknown. Using detailed structural analysis by X-ray crystallography we reveal the sophisticated and cyclic enzymatic cascade deployed by Pseudoalteromonas distincta (strain U2A) to utilize λ-carrageenan. The cascade incorporates ten glycoside hydrolases and five sulfatases that are specific for λ-carrageenan and cooperate to completely deconstruct this polysaccharide, thus yielding galactose monosaccharides for subsequent energy production. The detailed molecular understanding of λ-carrageenan depolymerisation provided includes structural evidence for a lesser described sulfatase catalytic mechanism and elucidation of a distinct catabolic cascade that is unique from previously described carrageenan metabolic pathways. This insight also holds potential for the application of enzymatic logic in the generation of high value products from abundant natural biopolymers, such as carrageenans.

Keywords:  Pseudoalteromonas; carbohydrate metabolism; carrageenan; glycoside hydrolase; sulfatase

DOI:  https://doi.org/10.1016/j.jbc.2025.110719
Cell Host Microbe. 2025 Sep 16. pii: S1931-3128(25)00340-3. [Epub ahead of print]

Gut-microbiota-derived indole sulfate promotes heart failure in chronic kidney disease.

Yun Zhang, Xuejie Han, Tao Feng, Zewen Li, Hui Yu, Ye Chen, Yunlong Gao, Qianhui Gao, Linwei Zhang, Shanshan Li, Ling Shi, Xiru Zhang, Zhuang Li, Yue Li, Hongwei Zhou.

  Heart failure (HF) is highly prevalent in chronic kidney disease (CKD) and associates with alterations in gut microbiota, although the underlying mechanisms remain unclear, complicating diagnosis and treatment. In this study, we identify indoxyl sulfate (IS), produced by E. coli through the tryptophanase (TnaA) pathway, as a key metabolite involved in CKD-related HF. Mechanistically, IS disrupts cardiac mitochondrial function and induces myocardial apoptosis via the AHR-CYP1B1 axis, driving HF progression. To target this gut-microbiota-IS axis for clinical improvement of CKD-related HF, we applied probiotics to reduce E. coli abundance and IS levels, resulting in improved cardiac outcomes in rats and CKD patients. This study was registered at the Chinese Clinical Trial Register (https://www.chictr.org.cn: ChiCTR2500098366 and ChiCTR2500100588). Furthermore, E. coli abundance shows diagnostic potential for early prediction of HF onset within 6 months in a prospective CKD cohort study. These findings underscore the critical role of gut microbiota in CKD-related HF and suggest a microbiota-targeted therapeutic and diagnostic strategy for clinical intervention.

Keywords:  Escherichia coli; chronic kidney disease; heart failure; indoxyl sulfate

DOI:  https://doi.org/10.1016/j.chom.2025.08.014
Carbohydr Polym. 2025 Dec 01. pii: S0144-8617(25)01093-8. [Epub ahead of print]369 124308

Sulphated polysaccharides and biomaterials: Steering stem cell fate.

Deepika Bhat K, Yashaswini Devi G V, Joel Rimson Pinto, Bipasha Bose, Sudheer Shenoy P.

  Stem cells possess remarkable capabilities of self-renewal and differentiation into diverse specialized cell types, making them invaluable for regenerative medicine and tissue engineering. Their fate is governed by intrinsic genetic programs and extrinsic environmental cues, including biomaterials that mimic the natural extracellular matrix (ECM). Among these, naturally derived biomaterials such as sulphated polysaccharides have gained attention for their biocompatibility, biodegradability, and biological activity. Natural sulphated polysaccharides, including glycosaminoglycans (GAGs) derived from animal ECM and polysaccharides from marine algae, have emerged as potent modulators of stem cell fate. This review explores the influence of key sulphated GAGs-heparan sulphate and chondroitin sulphate-and marine-derived polysaccharides such as fucoidan, carrageenan, and ulvan on stem cell differentiation. These biopolymers, regulate critical cell signalling pathways involved in osteogenesis, adipogenesis, chondrogenesis, myogenesis, and neurogenesis which has been summarized in this review.

Keywords:  Carrageenan; Chondroitin sulphate; Differentiation; Fucoidan; Heparan sulphate; Stem cells; Ulvan

DOI:  https://doi.org/10.1016/j.carbpol.2025.124308