Shant Kumar

Hyaluronan (HA) has traditionally been viewed as a structural component of the extracellular matrix, valued primarily for its viscoelastic, lubricating, and hydrating properties. However, accumulating evidence suggests that ultra-high-molecular-weight hyaluronan (UHMW-HA) functions far beyond passive tissue support, acting as a dynamic regulator of inflammation, mechanotransduction, immune homeostasis, cellular senescence, and regeneration. In this narrative review, we examine HA and specifically focus upon UHMW-HA operating as a “living hydrogel”, an adaptive regenerative macromolecule that continuously interacts with its microenvironment to shape tissue function and resilience. We examine evidence spanning evolutionary biology, glycobiology, biomaterials science, and regenerative medicine to examine how polymer size encodes biological activity and how UHMW-HA influences stem cell behaviour, extracellular matrix remodelling, and responses to injury and ageing. Attention is given to unique biological models, including the naked mole-rat, whose exceptional longevity and cancer resistance have been linked to abundant UHMW-HA, offering insights into the relationship between extracellular matrix architecture and organismal health. We further discuss how advances in synthetic biology and biomaterials engineering are enabling the development of next-generation HA-based hydrogels that mimic these adaptive properties for therapeutic applications in tissue engineering, in addition to potential roles in dynamically optimizing wound repair, and musculoskeletal rejuvenation, through precision medicine approaches. Finally, we argue that reclassifying UHMW-HA as a living regenerative material rather than an inert scaffold provides a new concept for designing bioinspired therapeutics and understanding extracellular matrix function. This review demonstrates HA-adaptive macromolecules as critical entities in future regenerative strategies and highlights the specific and unique potential of UHMW-HA to combine material science developments with enhancement of preferable biological outcome.

Hyaluronan (HA) has traditionally been viewed as a structural component of the extracellular matrix, valued primarily for its viscoelastic, lubricating, and hydrating properties. However, accumulating evidence suggests that ultra-high molecular weight hyaluronan (UHMW-HA) functions far beyond passive tissue support, acting as a dynamic regulator of inflammation, mechanotransduction, immune homeostasis, cellular senescence, and regeneration. In this narrative review, we examine HA and specifically focus upon UHMW-HA operating as a “living hydrogel”, an adaptive regenerative macromolecule that continuously interacts with its microenvironment to shape tissue function and resilience. We examine evidence spanning evolutionary biology, glycobiology, biomaterials science, and regenerative medicine to examine how polymer size encodes biological activity and how UHMW-HA influences stem cell behaviour, extracellular matrix remodelling, and responses to injury and ageing. Attention is given to unique biological models, including the naked mole-rat, whose exceptional longevity and cancer resistance have been linked to abundant UHMW-HA, offering insights into the relationship between extracellular matrix architecture and organismal health. We further discuss how advances in synthetic biology and biomaterials engineering are enabling the development of next-generation HA-based hydrogels that mimic these adaptive properties for therapeutic applications in tissue engineering, in addition to potential roles in dynamically optimising wound repair, and musculoskeletal rejuvenation, through precision medicine approaches. Finally, we argue that reclassifying UHMW-HA as a living regenerative material rather than an inert scaffold provides a new concept for designing bioinspired therapeutics and understanding extracellular matrix function. This review demonstrates HA-adaptive macromolecules as critical entities in future regenerative strategies and highlights the specific and unique potential of UHMW-HA to combine material science developments with enhancement of preferable biological outcome.

Transcription factor PAX3/Pax3 contributes to diverse cell lineages during embryonic development and is important in tumourigenesis. We found that PAX3 is re‐expressed in neuroblastoma and malignant neuroblastic (N‐type) neuroblastoma cells had significantly higher PAX3 protein expression than their benign substrate‐adherent (S‐type) counterparts. Knock‐down of PAX3 expression by siRNA transfection resulted in persistent cell growth inhibition in both types of neuroblastoma cell, owing to G1 cell cycle arrest and progressive apoptosis. Inhibition of PAX3 expression significantly decreased the attachment of S‐type SH‐EP1 cells to extra‐cellular matrix proteins, fibronectin, laminin and collagen IV. Migration and invasion of both neuroblastoma cell types were markedly reduced after PAX3 down‐regulation. PAX3 knock‐down significantly augmented the cytotoxic effect of chemotherapeutic agents, etoposide, vincristine and cisplatin, commonly used to treat neuroblastoma. Microarray analyses revealed that particularly signalling pathways involving cell cycle, apoptosis, cell adhesion, cytoskeletal remodelling and development were altered by PAX3 down‐regulation. Changes in PAX3 downstream genes identified by microarray analyses were validated in 47 genes by quantitative PCR. These novel findings lead us to propose that PAX3 might contribute to oncogenic characteristics of neuroblastoma cells by regulating a variety of crucial signalling pathways.

BackgroundVenous thromboembolism (VTE) following breast cancer chemotherapy is common. Chemotherapy-induced alterations in markers of haemostasis occur during chemotherapy. In this study we investigated the changes in serum and plasma VEGF, together with platelet release of VEGF and related these to the development of VTE at 3 months. MethodsSerum and plasma VEGF, together with platelet release of VEGF were measured prior to chemotherapy and at 24 hours; four-, eight days and three months following commencement of chemotherapy in early and advanced breast cancer patients and in age and sex matched controls. Duplex ultrasound imaging was performed after one month or if symptomatic. ResultsOf 123 patients 9.8% developed VTE within three months. Serum and plasma VEGF were increased in advanced breast cancer as was platelet release of VEGF. Prior to chemotherapy a 100 μg/ml increase in serum VEGF was associated with a 40% increased risk of VTE, while a 10 μg/ml increase in plasma VEGF was associated with a 20% increased risk of VTE. Serum VEGF showed a different response to chemotherapy in those who developed VTE. ConclusionA group of patients at risk of VTE could be identified, allowing targeted thrombopropylaxis. Whether or not the response in VEGF during chemotherapy has any angiogenic significance remains to be elucidated.

There is growing evidence that, because of the highly significant differences in gene activation/protein expression between animal models of stroke and stroke patients, the current treatment...