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This review highlights the multifunctional properties of perlecan (HSPG2) and its potential roles in repair biology. Perlecan is ubiquitous, occurring in vascular, cartilaginous, adipose, lymphoreticular, bone and bone marrow stroma and in neural tissues. Perlecan has roles in angiogenesis, tissue development and extracellular matrix stabilization in mature weight bearing and tensional tissues. Perlecan contributes to mechanosensory properties in cartilage through pericellular interactions with fibrillin-1, type IV, V, VI and XI collagen and elastin. Perlecan domain I - FGF, PDGF, VEGF and BMP interactions promote embryonic cellular proliferation, differentiation, and tissue development. Perlecan domain II, an LDLR-like domain interacts with lipids, Wnt and Hedgehog morphogens. Perlecan domain III binds FGF-7 and 18 and has roles in the secretion of perlecan. Perlecan domain IV, an immunoglobulin repeat domain, has cell attachment and matrix stabilizing properties. Perlecan domain V promotes tissue repair through interactions with VEGF, VEGF-R2 and α2β1 integrin. Perlecan domain-V LG1-LG2 and LG3 fragments antagonize these interactions. Perlecan domain V promotes reconstitution of the blood brain barrier damaged by ischemic stroke and is neurogenic and neuroprotective. Perlecan-VEGF-VEGFR2, perlecan-FGF-2 and perlecan-PDGF interactions promote angiogenesis and wound healing. Perlecan domain I, III and V interactions with platelet factor-4 and megakaryocyte and platelet inhibitory receptor promote adhesion of cells to implants and scaffolds in vascular repair. Perlecan localizes acetylcholinesterase in the neuromuscular junction and is of functional significance in neuromuscular control. Perlecan mutation leads to Schwartz-Jampel Syndrome, functional impairment of the biomechanical properties of the intervertebral disc, variable levels of chondroplasia and myotonia. A greater understanding of the functional working of the neuromuscular junction may be insightful in therapeutic approaches in the treatment of neuromuscular disorders. Tissue engineering of salivary glands has been undertaken using bioactive peptides (TWSKV) derived from perlecan domain IV. Perlecan TWSKV peptide induces differentiation of salivary gland cells into self-assembling acini-like structures that express salivary gland biomarkers and secrete α-amylase. Perlecan also promotes chondroprogenitor stem cell maturation and development of pluripotent migratory stem cell lineages, which participate in diarthrodial joint formation, and early cartilage development. Recent studies have also shown that perlecan is prominently expressed during repair of adult human articular cartilage. Perlecan also has roles in endochondral ossification and bone development. Perlecan domain I hydrogels been used in tissue engineering to establish heparin binding growth factor gradients that promote cell migration and cartilage repair. Perlecan domain I collagen I fibril scaffolds have also been used as an FGF-2 delivery system for tissue repair. With the availability of recombinant perlecan domains, the development of other tissue repair strategies should emerge in the near future. Perlecan co-localization with vascular elastin in the intima, acts as a blood shear-flow endothelial sensor that regulates blood volume and pressure and has a similar role to perlecan in canalicular fluid, regulating bone development and remodeling. This complements perlecan’s roles in growth plate cartilage and in endochondral ossification to form the appendicular and axial skeleton. Perlecan is thus a ubiquitous, multifunctional, and pleomorphic molecule of considerable biological importance. A greater understanding of its diverse biological roles and functional repertoires during tissue development, growth and disease will yield valuable insights into how this impressive proteoglycan could be utilized successfully in repair biology.

Mechanical stress plays a critical role in cartilage development and homoeostasis. Chondrocytes are surrounded by a narrow pericellular matrix (PCM), which absorbs dynamic and static forces and transmits them to the chondrocyte surface. Recent studies have demonstrated that molecular components, including perlecan, collagen and hyaluronan, provide distinct physical properties for the PCM and maintain the essential microenvironment of chondrocytes. These physical signals are sensed by receptors and molecules located in the cell membrane, such as Ca2+ channels, the primary cilium and integrins, and a series of downstream molecular pathways are involved in mechanotransduction in cartilage. All mechanoreceptors convert outside signals into chemical and biological signals, which then regulate transcription in chondrocytes in response to mechanical stresses. This review highlights recent progress and focuses on the function of the PCM and cell surface molecules in chondrocyte mechanotransduction. Emerging understanding of the cellular and molecular mechanisms that regulate mechanotransduction will provide new insights into osteoarthritis pathogenesis and precision strategies that could be used in its treatment.

Heterogeneous subtypes of cancer-associated fibroblasts (CAFs) coexist within pancreatic cancer tissues and can both promote and restrain disease progression. Here, we interrogate how cancer cells harboring distinct alterations in p53 manipulate CAFs. We reveal the existence of a p53-driven hierarchy, where cancer cells with a gain-of-function (GOF) mutant p53 educate a dominant population of CAFs that establish a pro-metastatic environment for GOF and null p53 cancer cells alike. We also demonstrate that CAFs educated by null p53 cancer cells may be reprogrammed by either GOF mutant p53 cells or their CAFs. We identify perlecan as a key component of this pro-metastatic environment. Using intravital imaging, we observe that these dominant CAFs delay cancer cell response to chemotherapy. Lastly, we reveal that depleting perlecan in the stroma combined with chemotherapy prolongs mouse survival, supporting it as a potential target for anti-stromal therapies in pancreatic cancer. Subtypes of cancer associated fibroblasts can both promote and suppress tumorigenesis. Here, the authors investigate how p53 status in pancreatic cancer cells affects their interaction with cancer associated fibroblasts, and report perlecan as a mediator of the pro-metastatic environment.

The extracellular matrix (ECM) has long been regarded as a packing material; supporting cells within the tissue and providing tensile strength and protection from mechanical stress. There is little surprise when one considers the dynamic nature of many of the individual proteins that contribute to the ECM, that we are beginning to appreciate a more nuanced role for the ECM in tissue homeostasis and disease. Articular cartilage is adapted to be able to perceive and respond to mechanical load. Indeed, physiological loads are essential to maintain cartilage thickness in a healthy joint and excessive mechanical stress is associated with the breakdown of the matrix that is seen in osteoarthritis (OA). Although the trigger by which increased mechanical stress drives catabolic pathways remains unknown, one mechanism by which cartilage responds to increased compressive load is by the release of growth factors that are sequestered in the pericellular matrix. These are heparan sulfate-bound growth factors that appear to be largely chondroprotective and displaced by an aggrecan-dependent sodium flux. Emerging evidence suggests that the released growth factors act in a coordinated fashion to drive cartilage repair. Thus, we are beginning to appreciate that the ECM is the key mechano-sensor and mechano-effector in cartilage, responsible for directing subsequent cellular events of relevance to joint health and disease.

In this editorial to MDPI Pharmaceuticals special issue “Glycosaminoglycans and Proteoglycans” we describe in outline the common structural features of glycosaminoglycans and the characteristics of proteoglycans, including the intracellular proteoglycan, serglycin, cell-surface proteoglycans, like syndecans and glypicans, and the extracellular matrix proteoglycans, like aggrecan, perlecan, and small leucine-rich proteoglycans. The context in which the pharmaceutical uses of glycosaminoglycans and proteoglycans are presented in this special issue is given at the very end.

In this study, we review mechanoregulatory roles for perlecan in load-bearing connective tissues. Perlecan facilitates the co-acervation of tropoelastin and assembly of elastic microfibrils in translamellar cross-bridges which, together with fibrillin and elastin stabilise the extracellular matrix of the intervertebral disc annulus fibrosus. Pericellular perlecan interacts with collagen VI and XI to define and stabilize this matrix compartment which has a strategic position facilitating two-way cell-matrix communication between the cell and its wider extracellular matrix. Cues from the extracellular matrix are fed through this pericellular matrix back to the chondrocyte, allowing it to perceive and respond to subtle microenvironmental changes to regulate tissue homeostasis. Thus perlecan plays a key regulatory role in chondrocyte metabolism, and in chondrocyte differentiation. Perlecan acts as a transport proteoglycan carrying poorly soluble, lipid-modified proteins such as the Wnt or Hedgehog families facilitating the establishment of morphogen gradients that drive tissue morphogenesis. Cell surface perlecan on endothelial cells or osteocytes acts as a flow sensor in blood and the lacunar canalicular fluid providing feedback cues to smooth muscle cells regulating vascular tone and blood pressure, and the regulation of bone metabolism by osteocytes highlighting perlecan’s multifaceted roles in load-bearing connective tissues.

Localised breast cancer can be cured by surgery and adjuvant treatments, but mortality remains high as some tumours metastasize early. Perlecan is a basement membrane (BM) protein involved in tumour development and progression. Here, mRNA and protein expression of perlecan, and mRNA expression of matrix degrading enzymes were studied in normal breast and invasive breast cancer, and correlated to prognostic risk factors, in particular oestrogen status. Moreover, plasma levels of perlecan were measured in patients with breast cancer and compared with controls. mRNA data was extracted from the Cancer Genome Atlas database. Perlecan protein expression was visualized using immunofluorescence and plasma levels measured by ELISA assay. Perlecan mRNA levels were twice as high in normal breast compared with breast cancer tissue. A strong correlation was found between mRNA expression of perlecan and several matrix-degrading enzymes in oestrogen receptor positive (ER+) tumours. Perlecan protein was localized to both epithelial and vascular BMs, but absent in the stroma in normal breast. In breast cancer, the expression of perlecan in epithelial BM was fragmented or completely lost, with a marked upregulation of perlecan expression in the stroma. Significantly higher levels of perlecan were found in plasma of ER+ patients when compared with ER- patients. This study shows that perlecan expression and degradation in breast cancer may be linked to the ER status of the tumour.

Glycosaminoglycans are major components of brain extracellular matrix (ECM), although heparan sulfate (HS) contribution in brain physiology and carcinogenesis remains underinvestigated. This study examined HS content and distribution in glioblastoma multiforme (GBM) tissues in the context of potential molecular mechanisms underlying its deregulation in brain tumours. Totally, 42 tissue samples and paraffin-embedded tissues for 31 patients with different prognosis were investigated. HS expression was demonstrated in 50–55% of the GBM tumours by immunohistochemistry (IHC), while almost no HS content was detected in the surrounding paratumourous brain tissues. Heterogeneous HS distribution in the HS-positive tumours was more related to the necrosis or glandular-like brain zones rather than glioma cells with high or low Ki-67 index. According the Kaplan–Meier curves, HS accumulation in glioma cells was associated with low relapse-free survival (RS) of the GBM patients (p < 0.05) and was likely to be due to the increased transcriptional activity of HSPG core proteins (syndecan-1, 2–3 fold; glypican-1, 2,5 fold; perlecan/HSPG2, 13–14 fold). Activation of perlecan/HSPG2 expression correlated with the patients’ survival according Kaplan–Meier (p = 0.0243) and Cox proportional-hazards regression (HR = 3.1; P(Y) = 0.03) analyses, while up-regulation of syndecan-1 and glypican-1 was not associated with the patients survival. Taken together, the results indicate that increase of HS content and up-regulation of perlecan/HSPG2 expression in glioblastoma tissues contribute to tumour development through the transformation of brain extracellular matrix into tumour microenvironment, and represent negative prognostic factors for glioblastoma progression.

Background Neurodegenerative disorders are a group of age-associated diseases characterized by progressive degeneration of the structure and function of the CNS. Two key pathological features of these disorders are blood-brain barrier (BBB) breakdown and protein aggregation. Main body The BBB is composed of various cell types and a non-cellular component---the basal lamina (BL). Although how different cells affect the BBB is well studied, the roles of the BL in BBB maintenance and function remain largely unknown. In addition, located in the perivascular space, the BL is also speculated to regulate protein clearance via the meningeal lymphatic/glymphatic system. Recent studies from our laboratory and others have shown that the BL actively regulates BBB integrity and meningeal lymphatic/glymphatic function in both physiological and pathological conditions, suggesting that it may play an important role in the pathogenesis and/or progression of neurodegenerative disorders. In this review, we focus on changes of the BL and its major components during aging and in neurodegenerative disorders, including Alzheimer’s disease (AD), Parkinson’s disease (PD), and amyotrophic lateral sclerosis (ALS). First, we introduce the vascular and lymphatic systems in the CNS. Next, we discuss the BL and its major components under homeostatic conditions, and summarize their changes during aging and in AD, PD, and ALS in both rodents and humans. The functional significance of these alterations and potential therapeutic targets are also reviewed. Finally, key challenges in the field and future directions are discussed. Conclusions Understanding BL changes and the functional significance of these changes in neurodegenerative disorders will fill the gap of knowledge in the field. Our goal is to provide a clear and concise review of the complex relationship between the BL and neurodegenerative disorders to stimulate new hypotheses and further research in this field.

Despite recent therapeutic advancements, ischemic stroke remains a major cause of death and disability. It has been previously demonstrated that  ~ 85-kDa recombinant human perlecan domain V (rhPDV) binds to upregulated integrin receptors (α2β1 and α5β1) associated with neuroprotective and functional improvements in various animal models of acute ischemic stroke. Recombinant human perlecan laminin-like globular domain 3 (rhPDV LG3 ), a 21-kDa C-terminal subdomain of rhPDV, has been demonstrated to more avidly bind to the α2β1 integrin receptor than its parent molecule and consequently was postulated to evoke significant neuroprotective and functional effects. To test this hypothesis, fifty male C57Bl/6 J mice studied in a t-MCAO model were randomly allocated to either rhPDV treatment, rhPDV LG3 , or equivalent volume of PBS at the time of reperfusion in a study where all procedures and analyses were conducted blind to treatment. On post-MCAO day 7, 2,3,5-triphenyltetrazolium chloride staining of brain slices was used to quantify infarct volume. We observed that treatment with rhPDV LG3 reduced infarct volume by 65.6% ( p  = 0.0001), improved weight loss ( p  < 0.05), and improved functional outcome measures ( p  < 0.05) when compared to PBS controls, improvements which were generally greater in magnitude than those observed for 2 mg/kg of rhPDV. In addition, treatment with 6 mg/kg of rhPDV LG3 was observed to significantly reduce mortality due to stroke in one model, an outcome not previously observed for rhPDV. Our initial findings suggest that treatment with rhPDV LG3 provides significant improvement in neuroprotective and functional outcomes in experimental stroke models and that further investigation of rhPDV LG3 as a novel neuroprotective therapy for patients with stroke is warranted.