Heparan Sulfate Proteoglycans: Key Mediators of Stem Cell Function

Ravikumar, Maanasa; Smith, Raymond A.; Nurcombe, Victor; Cool, Simon M.

doi:10.3389/fcell.2020.581213

Cited by 27 publications

(22 citation statements)

References 275 publications

(303 reference statements)

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Section: Discussionmentioning

confidence: 99%

“…The importance of HSPG molecules in stem cell regulation has been emphasized in recent studies (Ravikumar et al., 2020). However, the function of HSPGs in the adult stem cell niche remains poorly understood (Ravikumar et al., 2020). Overall, our (previous and current) work provides evidence that three different core proteins work together to form a stable and precise adult stem cell niche, thus deepening our understanding of the evolutionarily conserved mechanisms in the regulation of the adult stem cell niche.…”

Section: Discussionmentioning

confidence: 99%

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Heparan sulfate proteoglycan molecules, syndecan and perlecan, have distinct roles in the maintenance of Drosophila germline stem cells

et al. 2021

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The Drosophila female germline stem cell (GSC) niche provides an excellent model for understanding the stem cell niche in vivo. The GSC niche is composed of stromal cells that provide growth factors for the maintenance of GSCs and the associated extracellular matrix (ECM). Although the function of stromal cells/growth factors has been well studied, the function of the ECM in the GSC niche is largely unknown. In this study, we investigated the function of syndecan and perlecan, molecules of the heparan sulfate proteoglycan (HSPG) family, as the main constituents of the ECM. We found that both of these genes were expressed in niche stromal cells, and knockdown of them in stromal cells decreased GSC number, indicating that these genes are important niche components. Interestingly, our genetic analysis revealed that the effects of syndecan and perlecan on the maintenance of GSC were distinct. While the knockdown of perlecan in the GSC niche increased the number of cystoblasts, a phenotype suggestive of delayed differentiation of GSCs, the same was not true in the context of syndecan. Notably, the overexpression of syndecan and perlecan did not cause an expansion of the GSC niche, opposing the results reported in the context of glypican, another HSPG gene. Altogether, our data suggest that HSPG genes contribute to the maintenance of GSCs through multiple mechanisms, such as the control of signal transduction, and ligand distribution/stabilization. Therefore, our study paves the way for a deeper understanding of the ECM functions in the stem cell niche.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Heparan sulfate proteoglycan molecules, syndecan and perlecan, have distinct roles in the maintenance of Drosophila germline stem cells

et al. 2021

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“…For example, oxidation of carbohydrates, such as glycosaminoglycans (GAGs), by free radicals exacerbates ECM restructuring and contributes to altered cell behavior ( Rees et al., 2008 ). GAGs, particularly heparan sulfate (HS), have an important role in mediating stem cell function ( Ravikumar et al., 2020 ). HS can bind and sequester chemokines, cytokines, and growth factors to the ECM; regulate their bioavailability; and potentiate their binding with cognate cell-surface receptors for signaling ( Xu and Esko, 2014 ).…”

Section: Main Textmentioning

confidence: 99%

Age-Related Changes in the Inflammatory Status of Human Mesenchymal Stem Cells: Implications for Cell Therapy

et al. 2021

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Human mesenchymal stem/stromal cell (hMSC)-based cell therapies are promising for treating a variety of diseases. The unique immunomodulatory properties of hMSCs have extended their therapeutic potential beyond tissue regeneration. However, extensive pre-clinical culture expansion inevitably drives cells toward replicative “aging” and a consequent decline in quality. These “ in vitro -aged” hMSCs resemble biologically aged cells, which have been reported to show senescence signatures, diminished immunosuppressive capacity, and weakened regenerative potential as well as pro-inflammatory features. In this review, we have surveyed the literature to explore the intimate relationship between the inflammatory status of hMSCs and their in vitro aging process. We posit that a shift from an anti-inflammatory to a pro-inflammatory phenotype of culture-expanded hMSCs contributes to a deterioration in their therapeutic efficacy. Potential molecular and cellular mechanisms underpinning this phenomenon have been discussed. We have also highlighted studies that leverage these mechanisms to make culture-expanded hMSCs more amenable for clinical use.

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“…These two genes encode enzymes involved in the biosynthesis of heparan sulfate, a glycosaminoglycan typically conjugated to plasma membrane or extracellular matrix proteins. Heparan sulfate interacts with a variety of extracellular proteins and thereby modulates both mechanotransduction and signal transduction at the cell surface 30 . Within the antigen processing/presentation gene set, Tap1 and B2m were uniquely and dramatically depleted in our screen, ranking as the 41 st and 320 th most depleted genes, respectively (Fig.…”

Section: Resultsmentioning

confidence: 99%

Genome-scale CRISPR screening in a single mouse liver

2021

Preprint

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Our ability to understand and modulate mammalian physiology and disease requires knowing how all genes contribute to any given phenotype in the organism. Genome-wide screening using CRISPR-Cas9 has emerged as a powerful method for the genetic dissection of cellular processes1,2, but the need to stably deliver single guide RNAs to millions of cells has restricted its implementation to ex vivo systems. These ex vivo systems cannot reproduce all of the cellular phenotypes observed in vivo nor can they recapitulate all of the factors that influence these phenotypes. There thus remains a pressing need for high-throughput functional genomics in a living organism. Here, we establish accessible genome-wide screening in the mouse liver and use this approach to uncover the complete regulation of cellular fitness in a living organism. We discover novel sex-specific and cell non-autonomous regulation of cell growth and viability. In particular, we find that the class I major histocompatibility complex is essential for preventing immune-mediated clearance of hepatocytes. Our approach provides the first comprehensive picture of cell fitness in a living organism and highlights the importance of investigating cellular phenomena in their native context. Our screening method is robust, scalable, and easily adapted to examine diverse cellular processes using any CRISPR application. We have hereby established a foundation for high-throughput functional genomics in a living mammal, enabling unprecedented insight into mammalian physiology and disease.

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Heparan Sulfate Proteoglycans: Key Mediators of Stem Cell Function

Cited by 27 publications

References 275 publications

Heparan sulfate proteoglycan molecules, syndecan and perlecan, have distinct roles in the maintenance of Drosophila germline stem cells

Heparan sulfate proteoglycan molecules, syndecan and perlecan, have distinct roles in the maintenance of Drosophila germline stem cells

Age-Related Changes in the Inflammatory Status of Human Mesenchymal Stem Cells: Implications for Cell Therapy

Genome-scale CRISPR screening in a single mouse liver

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