Fibrinogen-Derived γ377-395 Peptide Improves Cognitive Performance and Reduces Amyloid-β Deposition, without Altering Inflammation, in AβPP/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-β aggregation. Here we provide evidence regarding cognitive improvement and reduction of brain parenchyma amyloid-β deposition in AβPP/PS1 mice after treatment for one month with the fibrinogen-blocking peptide Fibγ377-395. No alteration in glial response or other neuroinflammatory markers was observed in the cortex of treated animals. Considering these results and the fact that Fibγ377-395 does not affect coagulation function, this peptide could be considered as a promising and safe candidate for chronic treatment of Alzheimer's disease

The ins and outs of muscle stem cell aging

Skeletal muscle has a remarkable capacity to regenerate by virtue of its resident stem cells (satellite cells). This capacity declines with aging, although whether this is due to extrinsic changes in the environment and/or to cell-intrinsic mechanisms associated to aging has been a matter of intense debate. Furthermore, while some groups support that satellite cell aging is reversible by a youthful environment, others support cell-autonomous irreversible changes, even in the presence of youthful factors. Indeed, whereas the parabiosis paradigm has unveiled the environment as responsible for the satellite cell functional decline, satellite cell transplantation studies support cell-intrinsic deficits with aging. In this review, we try to shed light on the potential causes underlying these discrepancies. We propose that the experimental paradigm used to interrogate intrinsic and extrinsic regulation of stem cell function may be a part of the problem. The assays deployed are not equivalent and may overburden specific cellular regulatory processes and thus probe different aspects of satellite cell properties. Finally, distinct subsets of satellite cells may be under different modes of molecular control and mobilized preferentially in one paradigm than in the other. A better understanding of how satellite cells molecularly adapt during aging and their context-dependent deployment during injury and transplantation will lead to the development of efficacious compensating strategies that maintain stem cell fitness and tissue homeostasis throughout life.Work in the authors’ laboratories was supported in part by grants from the US Institutes of National Health/n(R01AR060868 and R01AR061002) to ASB and by the Spanish Ministry of Economy and Innovation SAF2012-38547, SAF2015-67369-R, E-RARE, Marató-TV3, AFM, and EU-FP7 (Myoage and Endostem) to PMC

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

Understanding muscle regenerative decline with aging: new approaches to bring back youthfulness to aged stem cells

Aging is characterized by the progressive dysfunction of most tissues and organs, which has been linked to the regenerative decline of their resident stem cells over time. Skeletal muscle provides a stark example of this decline. Its stem cells, also called satellite cells, sustain muscle regeneration throughout life, but at advanced age they fail for largely undefined reasons. Here, we discuss current understanding of the molecular processes regulating satellite cell maintenance throughout life and how age-related failure of these processes contributes to muscle aging. We also highlight the emerging field of rejuvenating biology to restore features of youthfulness in satellite cells, with the ultimate goal of slowing down or reversing the age-related decline in muscle regeneration.Work in the authors’ laboratories has been supported by the following funding sources: The Spanish Ministry of Science, Innovation and Universities, Spain [grants RTI2018-096068-B-I00 and SAF 2015-70270-REDT, a María de Maeztu Unit of Excellence award to UPF (MDM-2014-0370), and a Severo Ochoa Center of Excellence award to the CNIC (SEV-2015-0505)], ERC-2016-AdG-741966, La Caixa-HEALTH (HR17-00040), MDA, UPGRADE-H2020-825825, AFM and DPP-E to PMC; JN and PSV acknowledge support from iMM start-up funding and ‘la Caixa’ Foundation for the Junior Leader Fellowship for PSV (LCF/BQ/PI19/11690006)

Proteostatic and metabolic control of stemness

Adult stem cells, particularly those resident in tissues with little turnover, are largely quiescent and only activate in response to regenerative demands, while embryonic stem cells continuously replicate, suggesting profoundly different regulatory mechanisms within distinct stem cell types. In recent years, evidence linking metabolism, mitochondrial dynamics, and protein homeostasis (proteostasis) as fundamental regulators of stem cell function has emerged. Here, we discuss new insights into how these networks control potency, self-renewal, differentiation, and aging of highly proliferative embryonic stem cells and quiescent adult stem cells, with a focus on hematopoietic and muscle stem cells and implications for anti-aging research.We thank Dr. E. Perdiguero for design and advice in artwork. P.M.-C. is supported by MINECO (SAF2015-67369-R, María de Maeztu Program for Units of Excellence to UPF [MDM-2014-0370], Severo Ochoa Program for Centers of Excellence to CNIC [SEV-2015-0505]), Convenio UPF-CNIC, ERC-741538, AFM, E-Rare/Eranet, MDA, Fundació Marató-TV3, and DPPE. P.S.-V. is supported by the Glenn Foundation for Medical Research. The authors apologize for work not being mentioned owing to space restrictions

Cilia control fat deposition during tissue repair

Fibro/adipogenic progenitors (FAPs) are emerging as crucial regulators of fibrous and fat deposits during skeletal muscle regeneration. In a recent issue of Cell, Kopinke et al. (2017) report that primary cilia induce the adipogenic fate of FAPs in injured and diseased muscle by restraining Hedgehog signaling

Proteostatic and metabolic control of stemness

Adult stem cells, particularly those resident in tissues with little turnover, are largely quiescent and only activate in response to regenerative demands, while embryonic stem cells continuously replicate, suggesting profoundly different regulatory mechanisms within distinct stem cell types. In recent years, evidence linking metabolism, mitochondrial dynamics, and protein homeostasis (proteostasis) as fundamental regulators of stem cell function has emerged. Here, we discuss new insights into how these networks control potency, self-renewal, differentiation, and aging of highly proliferative embryonic stem cells and quiescent adult stem cells, with a focus on hematopoietic and muscle stem cells and implications for anti-aging research.We thank Dr. E. Perdiguero for design and advice in artwork. P.M.-C. is supported by MINECO (SAF2015-67369-R, María de Maeztu Program for Units of Excellence to UPF [MDM-2014-0370], Severo Ochoa Program for Centers of Excellence to CNIC [SEV-2015-0505]), Convenio UPF-CNIC, ERC-741538, AFM, E-Rare/Eranet, MDA, Fundació Marató-TV3, and DPPE. P.S.-V. is supported by the Glenn Foundation for Medical Research. The authors apologize for work not being mentioned owing to space restrictions

Circadian transcriptome processing and analysis: a workflow for muscle stem cells

Circadian rhythms coordinate biological processes with Earth's 24-h daily light/dark cycle. In the last years, efforts in the field of chronobiology have sought to understand the ways in which the circadian clock controls transcription across tissues and cells. This has been supported by the development of different bioinformatic approaches that allow the identification of 24-h oscillating transcripts. This workflow aims to describe how to isolate muscle stem cells for RNA sequencing analysis from a typical circadian experiment and introduces bioinformatic tools suitable for the analysis of circadian transcriptomes.H2020 Marie Skłodowska-Curie Actions. Grant Number: 89538