107 research outputs found
Understanding muscle stem cell regenerative decline with aging
Skeletal muscle has a remarkable capacity to regenerate by virtue of its resident Pax7-expressing stem cells (satellite cells), which are normally quiescent in the adult. Upon injury, quiescent satellite cells activate and proliferate, to subsequently differentiate and form new myofibers or self-renew to restore the quiescent satellite cell pool. Through a combination of global gene expression/bioinformatics and molecular/cellular assays, we found that resting satellite cells have basal autophagy activity, which is required to maintain the quiescent state. We will discuss the consequences of the autophagy failure in the regenerative potential of muscle stem cells, particularly in the context of aging
Fibrinogen-Derived Îł377-395 Peptide Improves Cognitive Performance and Reduces Amyloid-ÎČ Deposition, without Altering Inflammation, in AÎČPP/PS1 Mice
Fibrinogen has emerged as a promising therapeutic target against Alzheimer's disease because of its dual role in altered vascular function and amyloid-ÎČ aggregation. Here we provide evidence regarding cognitive improvement and reduction of brain parenchyma amyloid-ÎČ deposition in AÎČPP/PS1 mice after treatment for one month with the fibrinogen-blocking peptide FibÎł377-395. No alteration in glial response or other neuroinflammatory markers was observed in the cortex of treated animals. Considering these results and the fact that FibÎł377-395 does not affect coagulation function, this peptide could be considered as a promising and safe candidate for chronic treatment of Alzheimer's disease
Aberrant repair and fibrosis development in skeletal muscle
The repair process of damaged tissue involves the coordinated activities of several cell types in response to local and systemic signals. Following acute tissue injury, infiltrating inflammatory cells and resident stem cells orchestrate their activities to restore tissue homeostasis. However, during chronic tissue damage, such as in muscular dystrophies, the inflammatory-cell infiltration and fibroblast activation persists, while the reparative capacity of stem cells (satellite cells) is attenuated. Abnormal dystrophic muscle repair and its end stage, fibrosis, represent the final common pathway of virtually all chronic neurodegenerative muscular diseases. As our understanding of the pathogenesis of muscle fibrosis has progressed, it has become evident that the muscle provides a useful model for the regulation of tissue repair by the local microenvironment, showing interplay among muscle-specific stem cells, inflammatory cells, fibroblasts and extracellular matrix components of the mammalian wound-healing response. This article reviews the emerging findings of the mechanisms that underlie normal versus aberrant muscle-tissue repair
Context-dependent roles of cellular senescence in normal, aged, and disease states.
Cellular senescence is a state of irreversible cell cycle arrest that often emerges after tissue damage and in age-related diseases. Through the production of a multicomponent secretory phenotype (SASP), senescent cells can impact the regeneration and function of tissues. However, the effects of senescent cells and their SASP are very heterogeneous and depend on the tissue environment and type as well as the duration of injury, the degree of persistence of senescent cells and the organism's age. While the transient presence of senescent cells is widely believed to be beneficial, recent data suggest that it is detrimental for tissue regeneration after acute damage. Furthermore, although senescent cell persistence is typically associated with the progression of age-related chronic degenerative diseases, it now appears to be also necessary for correct tissue function in the elderly. Here, we discuss what is currently known about the roles of senescent cells and their SASP in tissue regeneration in ageing and age-related diseases, highlighting their (negative and/or positive) contributions. We provide insight for future research, including the possibility of senolytic-based therapies and cellular reprogramming, with aims ranging from enhancing tissue repair to extending a healthy lifespan.Work in the authorsâ laboratory is supported by
MINECO-Spain (RTI2018-096068), H2020 European
Research Council-2016-AdG-741966, LaCaixaHEALTH-HR17-00040, MWRF, French Muscular
Dystrophy Association, Muscular Dystrophy Association, Fundacio LaMaratĂł TV3 (80/19-202021 and 137/
38-202033) and UPGRADE-H2020-825825; and
MarĂa-de-Maeztu-Program for Units of Excellence to
UPF (MDM-2014-0370), Severo Ochoa-Program for
Centers of Excellence to CNIC (SEV-2015-0505).S
uPA deficiency exacerbates muscular dystrophy in MDX mice
Duchenne muscular dystrophy (DMD) is a fatal and incurable muscle degenerative disorder. We identify a function of the protease urokinase plasminogen activator (uPA) in mdx mice, a mouse model of DMD. The expression of uPA is induced in mdx dystrophic muscle, and the genetic loss of uPA in mdx mice exacerbated muscle dystrophy and reduced muscular function. Bone marrow (BM) transplantation experiments revealed a critical function for BM-derived uPA in mdx muscle repair via three mechanisms: (1) by promoting the infiltration of BM-derived inflammatory cells; (2) by preventing the excessive deposition of fibrin; and (3) by promoting myoblast migration. Interestingly, genetic loss of the uPA receptor in mdx mice did not exacerbate muscular dystrophy in mdx mice, suggesting that uPA exerts its effects independently of its receptor. These findings underscore the importance of uPA in muscular dystrophy
3-Deazaadenosine alleviates senescence to promote cellular fitness and cell therapy efficiency in mice
International audienc
FoxO maintains a genuine muscle stem-cell quiescent state until geriatric age
Tissue regeneration declines with ageing but little is known about whether this arises from changes in stem-cell heterogeneity. Here, in homeostatic skeletal muscle, we identify two quiescent stem-cell states distinguished by relative CD34 expression: CD34High, with stemness properties (genuine state), and CD34Low, committed to myogenic differentiation (primed state). The genuine-quiescent state is unexpectedly preserved into later life, succumbing only in extreme old age due to the acquisition of primed-state traits. Niche-derived IGF1-dependent Akt activation debilitates the genuine stem-cell state by imposing primed-state features via FoxO inhibition. Interventions to neutralize Akt and promote FoxO activity drive a primed-to-genuine state conversion, whereas FoxO inactivation deteriorates the genuine state at a young age, causing regenerative failure of muscle, as occurs in geriatric mice. These findings reveal transcriptional determinants of stem-cell heterogeneity that resist ageing more than previously anticipated and are only lost in extreme old age, with implications for the repair of geriatric muscle.The authors acknowledge funding from MINECO-Spain (grant no. RTI2018-096068), ERC2016-AdG-741966, LaCaixa-HEALTH-HR17-00040, MDA, UPGRADE-H2020-825825, AFM and DPP-Spain to P.M.-C; MarĂa-de-Maeztu-Program for Units of Excellence to UPF (grant no. MDM-2014-0370) and the Severo-Ochoa-Program for Centers of Excellence to CNIC (grant no. SEV-2015-0505). This work was also supported by NIAMS IRP through NIH grants nos AR041126 and AR041164 to V.S. and utilized computational resources of the NIH HPC Biowulf cluster (http://hpc.nih.gov); ASI, Ricerca Finalizzata, Ateneo Sapienza to A.M.; AIRC (grant no. 23257); ASI (grant no. MARS-PRE, DC-VUM-2017-006); H2020-MSCA-RISE-2014 (645648) to M.S. and a FNR core grant (grant no. C15/BM/10397420) to A.d.S. L.G.P. was partially supported by an FPI fellowship and an EMBO fellowship (grant no. ALTF 420-2017); and S.C., X.H. and V.M. by FI, Severo-Ochoa and PFI Fellowships (Spain), respectively
Spatiotemporal transcriptomic atlas of mouse organogenesis using DNA nanoball-patterned arrays.
Spatially resolved transcriptomic technologies are promising tools to study complex biological processes such as mammalian embryogenesis. However, the imbalance between resolution, gene capture, and field of view of current methodologies precludes their systematic application to analyze relatively large and three-dimensional mid- and late-gestation embryos. Here, we combined DNA nanoball (DNB)-patterned arrays and in situ RNA capture to create spatial enhanced resolution omics-sequencing (Stereo-seq). We applied Stereo-seq to generate the mouse organogenesis spatiotemporal transcriptomic atlas (MOSTA), which maps with single-cell resolution and high sensitivity the kinetics and directionality of transcriptional variation during mouse organogenesis. We used this information to gain insight into the molecular basis of spatial cell heterogeneity and cell fate specification in developing tissues such as the dorsal midbrain. Our panoramic atlas will facilitate in-depth investigation of longstanding questions concerning normal and abnormal mammalian development.This work is part of the ââSpatioTemporal Omics Consortiumââ (STOC) paper package. A list of STOC members is available at: http://sto-consortium.org. We would
like to thank the MOTIC China Group, Rongqin Ke (Huaqiao University, Xiamen,
China), Jiazuan Ni (Shenzhen University, Shenzhen, China), Wei Huang (Center
for Excellence in Brain Science and Intelligence Technology, Chinese Academy
of Sciences, Shanghai, China), and Jonathan S. Weissman (Whitehead Institute,
Boston, USA) for their help. This work was supported by the grant of Top Ten
Foundamental Research Institutes of Shenzhen, the Shenzhen Key Laboratory
of Single-Cell Omics (ZDSYS20190902093613831), and the Guangdong Provincial Key Laboratory of Genome Read and Write (2017B030301011); Longqi Liu
was supported by the National Natural Science Foundation of China
(31900466) and Miguel A. Estebanâs laboratory at the Guangzhou Institutes of
Biomedicine and Health by the Strategic Priority Research Program of the Chinese Academy of Sciences (XDA16030502), National Natural Science Foundation of China (92068106), and the Guangdong Basic and Applied Basic Research
Foundation (2021B1515120075).S
Cell transcriptomic atlas of the non-human primate Macaca fascicularis.
Studying tissue composition and function in non-human primates (NHPs) is crucial to understand the nature of our own species. Here we present a large-scale cell transcriptomic atlas that encompasses over 1 million cells from 45 tissues of the adult NHP Macaca fascicularis. This dataset provides a vast annotated resource to study a species phylogenetically close to humans. To demonstrate the utility of the atlas, we have reconstructed the cell-cell interaction networks that drive Wnt signalling across the body, mapped the distribution of receptors and co-receptors for viruses causing human infectious diseases, and intersected our data with human genetic disease orthologues to establish potential clinical associations. Our M.âfascicularis cell atlas constitutes an essential reference for future studies in humans and NHPs.We thank W. Liu and L. Xu from the Huazhen Laboratory Animal Breeding
Centre for helping in the collection of monkey tissues, D. Zhu and H. Li from the Bioland
Laboratory (Guangzhou Regenerative Medicine and Health Guangdong Laboratory) for
technical help, G. Guo and H. Sun from Zhejiang University for providing HCL and MCA gene
expression data matrices, G. Dong and C. Liu from BGI Research, and X. Zhang, P. Li and C. Qi
from the Guangzhou Institutes of Biomedicine and Health for experimental advice or providing
reagents. This work was supported by the Shenzhen Basic Research Project for Excellent
Young Scholars (RCYX20200714114644191), Shenzhen Key Laboratory of Single-Cell Omics
(ZDSYS20190902093613831), Shenzhen Bay Laboratory (SZBL2019062801012) and Guangdong Provincial Key Laboratory of Genome Read and Write (2017B030301011). In
addition, L.L. was supported by the National Natural Science Foundation of China (31900466),
Y. Hou was supported by the Natural Science Foundation of Guangdong Province
(2018A030313379) and M.A.E. was supported by a Changbai Mountain Scholar award
(419020201252), the Strategic Priority Research Program of the Chinese Academy of Sciences
(XDA16030502), a Chinese Academy of SciencesâJapan Society for the Promotion of Science
joint research project (GJHZ2093), the National Natural Science Foundation of China
(92068106, U20A2015) and the Guangdong Basic and Applied Basic Research Foundation
(2021B1515120075). M.L. was supported by the National Key Research and Development
Program of China (2021YFC2600200).S
Recommended from our members
240th ENMC workshop: the involvement of skeletal muscle stem cells in the pathology of muscular dystrophies 25 -27 January 2019, Hoofddorp, the Netherlands
Satellite cells are dysfunctional in several neuromuscular disorders.
Some muscles are more susceptible than others to disease and ageing.
In vitro and in vivo model systems have shed light on many of the processes involved.
in satellite cell function and dysfunction, but the drawbacks of each model system must
be considered.
Skeletal muscle pathology in mouse models of neuromuscular disease are affected by
genetic background.
A single cell approach will be useful to identify dysfunction in subsets of cell
populations
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