Aged skeletal stem cells generate an inflammatory degenerative niche

Ambrosi, Thomas H.; Marecic, Owen; McArdle, Adrian; Sinha, Rahul; Gulati, Gunsagar S.; Tong, Xinming; Wang, Yuting; Steininger, Holly; Hoover, Malachia; Koepke, Lauren S.; Murphy, Matthew P.; Sokol, Jan; Seo, Eun Young; Tevlin, Ruth; López, Michael; Brewer, Rachel; Mascharak, Shamik; Lu, Laura; Ajanaku, Oyinkansola; Conley, Stephanie D.; Seita, Jun; Morri, Maurizio; Neff, Norma; Sahoo, Debashis; Yang, Fan; Weissman, Irving L.; Longaker, Michael T.; Chan, Charles K.

doi:10.1038/s41586-021-03795-7

Cited by 219 publications

(182 citation statements)

References 55 publications

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“…BMP2 has been widely used in clinics for the treatment of bone fracture [ 43 , 44 ]. Gene therapy provides a powerful technology for prolonged delivery of BMP2 over stable periods of time to overcome the short half-lives of protein treatment [ 45 ].…”

Section: Discussionmentioning

confidence: 99%

Engineering stem cells to produce exosomes with enhanced bone regeneration effects: an alternative strategy for gene therapy

et al. 2022

J Nanobiotechnol

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Background Exosomes derived from stem cells have been widely studied for promoting regeneration and reconstruction of multiple tissues as “cell-free” therapies. However, the applications of exosomes have been hindered by limited sources and insufficient therapeutic potency. Results In this study, a stem cell-mediated gene therapy strategy is developed in which mediator mesenchymal stem cells are genetically engineered by bone morphogenetic protein-2 gene to produce exosomes (MSC-BMP2-Exo) with enhanced bone regeneration potency. This effect is attributed to the synergistic effect of the content derived from MSCs and the up-regulated BMP2 gene expression. The MSC-BMP2-Exo also present homing ability to the injured site. The toxic effect of genetical transfection vehicles is borne by mediator MSCs, while the produced exosomes exhibit excellent biocompatibility. In addition, by plasmid tracking, it is interesting to find a portion of plasmid DNA can be encapsulated by exosomes and delivered to recipient cells. Conclusions In this strategy, engineered MSCs function as cellular factories, which effectively produce exosomes with designed and enhanced therapeutic effects. The accelerating effect in bone healing and the good biocompatibility suggest the potential clinical application of this strategy. Graphical Abstract

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Section: Discussionmentioning

confidence: 99%

Engineering stem cells to produce exosomes with enhanced bone regeneration effects: an alternative strategy for gene therapy

et al. 2022

J Nanobiotechnol

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“…During aging, tissue-specific alterations in the niche synergize with stem cell-intrinsic changes to contribute to the development of age-associated traits 17,[70][71][72] . Aging has been proposed to drive a pro-inflammatory microenvironment that perturbs adult stem cell behavior in several tissues, including that of neural, skeletal and hematopoietic stem cells [73][74][75][76] . Interestingly, the nature of these signals is highly tissue-dependent and include infiltration of immune cells into the stem cell niche 73 , or a transcriptional switch of the stem cells that create a pro-inflammatory environment that negatively feeds back to their own fitness 74 .…”

Section: Discussionmentioning

confidence: 99%

“…Aging has been proposed to drive a pro-inflammatory microenvironment that perturbs adult stem cell behavior in several tissues, including that of neural, skeletal and hematopoietic stem cells [73][74][75][76] . Interestingly, the nature of these signals is highly tissue-dependent and include infiltration of immune cells into the stem cell niche 73 , or a transcriptional switch of the stem cells that create a pro-inflammatory environment that negatively feeds back to their own fitness 74 . Here, we have characterized for the first time, and in an unbiased manner, the effects of the pro-inflammatory cytokine IL-17 on an aging tissue-namely, skin.…”

Section: Discussionmentioning

confidence: 99%

Local IL-17 orchestrates skin aging

Solá

Mereu

Bonjoch

et al. 2022

Preprint

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Skin aging is characterized by structural and functional changes that lead to slower wound healing and higher rate of infections, which contribute to age-associated frailty. This likely depends on synergy between alterations in the local microenvironment and stem cell–intrinsic changes, underscored by pro-inflammatory microenvironments that drive pleotropic changes. To date, little is known about the precise nature and origin of the proposed age-associated inflammatory cues, or how they affect different tissue resident cell types. Based on deep single-cell RNA-sequencing of the entire dermal compartment, we now provide a comprehensive understanding of the age-associated changes in all skin cell types. We show a previously unreported skew towards an IL-17–expressing phenotype of Th cells, γδ T cells and innate lymphoid cells in aged skin. Aberrant IL-17 signaling is common to many autoimmune (e.g., rheumatoid arthritis and psoriasis) and chronic inflammatory diseases. Importantly, in vivo blockade of IL-17–triggered signaling during the aging process reduces the pro-inflammatory state by affecting immune and non-immune skin cells of both dermis and epidermis. Strikingly, IL-17 neutralization significantly delays the appearance of age-related traits, such as decreased epidermal thickness, increased cornified layer thickness and ameliorated hair follicle stem cell activation and hair shaft regeneration. Our results indicate that the aged skin shows chronic and persistent signs of inflammation, and that age-associated increased IL-17 signaling could be targeted as a strategy to prevent age-associated skin ailments in elderly.

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“…We also predict that investigations following the hallmarks of 'DNA damage', 'mitochondrial damage', 'cellular senescence', 'effect of ROS' and 'epigenetic alterations in the human transcriptome' will provide us with further evidence about the existing pathways and novel factors that may lead to potential targets for therapies in geriatric science. Aged SSCs promoted osteoclast activity and myeloid skewing in HSCs [82] Non-HSCs (MSCs) RNA a.…”

Section: Discussionmentioning

confidence: 99%

Aging, Bone Marrow and Next-Generation Sequencing (NGS): Recent Advances and Future Perspectives

Ganguly

Toghill²,

Pathak³

2021

IJMS

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The aging of bone marrow (BM) remains a very imperative and alluring subject, with an ever-increasing interest among fellow scientists. A considerable amount of progress has been made in this field with the established ‘hallmarks of aging’ and continued efforts to investigate the age-related changes observed within the BM. Inflammaging is considered as a low-grade state of inflammation associated with aging, and whilst the possible mechanisms by which aging occurs are now largely understood, the processes leading to the underlying changes within aged BM remain elusive. The ability to identify these changes and detect such alterations at the genetic level are key to broadening the knowledgebase of aging BM. Next-generation sequencing (NGS) is an important molecular-level application presenting the ability to not only determine genomic base changes but provide transcriptional profiling (RNA-seq), as well as a high-throughput analysis of DNA–protein interactions (ChIP-seq). Utilising NGS to explore the genetic alterations occurring over the aging process within alterative cell types facilitates the comprehension of the molecular and cellular changes influencing the dynamics of aging BM. Thus, this review prospects the current landscape of BM aging and explores how NGS technology is currently being applied within this ever-expanding field of research.

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Aged skeletal stem cells generate an inflammatory degenerative niche

Cited by 219 publications

References 55 publications

Engineering stem cells to produce exosomes with enhanced bone regeneration effects: an alternative strategy for gene therapy

Engineering stem cells to produce exosomes with enhanced bone regeneration effects: an alternative strategy for gene therapy

Local IL-17 orchestrates skin aging

Aging, Bone Marrow and Next-Generation Sequencing (NGS): Recent Advances and Future Perspectives

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