Pedro Victor - Academia.edu (original) (raw)

Papers by Pedro Victor

p38/MKP-1–regulated AKT coordinates macrophage transitions and resolution of inflammation during ... more p38/MKP-1–regulated AKT coordinates macrophage transitions and resolution of inflammation during tissue repair

Mechanisms of Ageing and Development, 2020

Aging is characterized by the functional and regenerative decline of tissues and organs. This reg... more Aging is characterized by the functional and regenerative decline of tissues and organs. This regenerative decline is a consequence of the numerical and functional loss of adult stem cells, which are the corner stone of tissue homeostasis and repair. A palpable example of this decline is provided by skeletal muscle, a specialized tissue composed of postmitotic myofibers that contract to generate force. Skeletal muscle stem cells (satellite cells) are long-lived and support muscle regeneration throughout life, but at advanced age they fail for largely undefined reasons. Here, we discuss recent advances in the understanding of how satellite cells integrate diverse intrinsic and extrinsic processes to ensure optimal homeostatic function and how this integration is perturbed during aging, causing regenerative failure. With this increased understanding, it is now feasible to design and test interventions that delay satellite cell aging. We discuss the exciting new therapeutic potential of integrating and combining distinct anti-aging strategies for regenerative medicine.

Stem cell (SC) lineages in barrier epithelia exhibit a high degree of plasticity. Mechanisms that... more Stem cell (SC) lineages in barrier epithelia exhibit a high degree of plasticity. Mechanisms that govern the precise specification of SC daughter cells during regenerative episodes are therefore critical to maintain homeostasis. One such common mechanism is the transient activation of the Notch (N) signaling pathway. N controls the choice between absorptive and entero-endocrine cell fates in both the mammalian small intestine and theDrosophilamidgut, yet how precisely N signaling promotes lineage restriction in progenitor cells remains unclear. Here, we describe a role for the WT1-like transcription factor Klumpfuss (Klu) in restricting the fate ofDrosophilaenteroblasts (EBs) downstream of N activation. Klu is transiently induced in Notch-positive EBs and its transient activity restricts cell fate towards the enterocyte (EC) lineage. Transcriptomics and DamID profiling show that Klu suppresses enteroendocrine (EE) cell fates by repressing E(Spl)m8-HLH and Phyllopod, both negative re...

Science (New York, N.Y.), 2016

Regenerative therapies are limited by unfavorable environments in aging and diseased tissues. A p... more Regenerative therapies are limited by unfavorable environments in aging and diseased tissues. A promising strategy to improve success is to balance inflammatory and anti-inflammatory signals and enhance endogenous tissue repair mechanisms. Here, we identified a conserved immune modulatory mechanism that governs the interaction between damaged retinal cells and immune cells to promote tissue repair. In damaged retina of flies and mice, platelet-derived growth factor (PDGF)-like signaling induced mesencephalic astrocyte-derived neurotrophic factor (MANF) in innate immune cells. MANF promoted alternative activation of innate immune cells, enhanced neuroprotection and tissue repair, and improved the success of photoreceptor replacement therapies. Thus, immune modulation is required during tissue repair and regeneration. This approach may improve the efficacy of stem-cell-based regenerative therapies.

Molecular Aspects of Medicine, 2016

Skeletal muscle mass and function decline with aging, a process known as sarcopenia, which restra... more Skeletal muscle mass and function decline with aging, a process known as sarcopenia, which restrains posture maintenance, mobility and quality of life in the elderly. Sarcopenia is also linked to a progressive reduction in the regenerative capacity of the skeletal muscle stem cells (satellite cells), which are critical for myofiber formation in early life stages and for sustaining repair in response to muscle damage or trauma. Here we will review the most recent findings on the causes underlying satellite cell functional decline with aging, and will discuss the prevalent view whereby age-associated extrinsic factor alterations impact negatively on satellite cell-intrinsic mechanisms, resulting in deficient muscle regeneration with aging. Further understanding of the interplay between satellite cell extrinsic and intrinsic factors in sarcopenia will facilitate therapies aimed at improving muscle repair in the increasing aging population.

Skeletal Muscle, 2016

Background: Extracellular stimuli induce gene expression responses through intracellular signalin... more Background: Extracellular stimuli induce gene expression responses through intracellular signaling mediators. The p38 signaling pathway is a paradigm of the mitogen-activated protein kinase (MAPK) family that, although originally identified as stress-response mediator, contributes to establishing stem cell differentiation fates. p38α is central for induction of the differentiation fate of the skeletal muscle stem cells (satellite cells) through not fully characterized mechanisms. Methods: To investigate the global gene transcription program regulated by p38α during satellite cell differentiation (myogenesis), and to specifically address whether this regulation occurs through direct action of p38α on gene promoters, we performed a combination of microarray gene expression and genome-wide binding analyses. For experimental robustness, two myogenic cellular systems with genetic and chemical loss of p38α function were used: (1) satellite cells derived from mice with muscle-specific deletion of p38α, and (2) the C2C12 murine myoblast cell line cultured in the absence or presence of the p38α/β inhibitor SB203580. Analyses were performed at cell proliferation and early differentiation stages. Results: We show that p38α binds to a large set of active promoters during the transition of myoblasts from proliferation to differentiation stages. p38α-bound promoters are enriched with binding motifs for several transcription factors, with Sp1, Tcf3/E47, Lef1, FoxO4, MyoD, and NFATc standing out in all experimental conditions. p38α association with chromatin correlates very well with high levels of transcription, in agreement with its classical function as an activator of myogenic differentiation. Interestingly, p38α also associates with genes repressed at the onset of differentiation, thus highlighting the relevance of p38-dependent chromatin regulation for transcriptional activation and repression during myogenesis. Conclusions: These results uncover p38α association and function on chromatin at novel classes of target genes during skeletal muscle cell differentiation. This is consistent with this MAPK isoform being a transcriptional regulator.

FEBS Journal, 2013

Aging of an organism is associated with the functional decline of tissues and organs, as well as ... more Aging of an organism is associated with the functional decline of tissues and organs, as well as a sharp decline in the regenerative capacity of stem cells. A prevailing view holds that the aging rate of an individual depends on the ratio of tissue attrition to tissue regeneration. Therefore, manipulations that favor the balance towards regeneration may prevent or delay aging. Skeletal muscle is a specialized tissue composed of postmitotic myofibers that contract to generate force. Satellite cells are the adult stem cells responsible for skeletal muscle regeneration. Recent studies on the biology of skeletal muscle and satellite cells in aging have uncovered the critical impact of systemic and niche factors on stem cell functionality and demonstrated the capacity of aged satellite cells to rejuvenate and increase their regenerative potential when exposed to a youthful environment. Here we review the current literature on the coordinated relationship between cell extrinsic and intrinsic factors that regulate the function of satellite cells, and ultimately determine tissue homeostasis and repair during aging, and which encourage the search for new anti-aging strategies.

The EMBO Journal, 2007

The p38 mitogen-activated protein kinase (MAPK) pathway plays a critical role in skeletal muscle ... more The p38 mitogen-activated protein kinase (MAPK) pathway plays a critical role in skeletal muscle differentiation. However, the relative contribution of the four p38 MAPKs (p38a, p38b, p38c and p38d) to this process is unknown. Here we show that myoblasts lacking p38a, but not those lacking p38b or p38d, are unable to differentiate and form multinucleated myotubes, whereas p38c-deficient myoblasts exhibit an attenuated fusion capacity. The defective myogenesis in the absence of p38a is caused by delayed cell-cycle exit and continuous proliferation in differentiation-promoting conditions. Indeed, activation of JNK/cJun was enhanced in p38a-deficient myoblasts leading to increased cyclin D1 transcription, whereas inhibition of JNK activity rescued the proliferation phenotype. Thus, p38a controls myogenesis by antagonizing the activation of the JNK proliferation-promoting pathway, before its direct effect on muscle differentiation-specific gene transcription. More importantly, in agreement with the defective myogenesis of cultured p38a D/D myoblasts, neonatal muscle deficient in p38a shows cellular hyperproliferation and delayed maturation. This study provides novel evidence of a fundamental role of p38a in muscle formation in vitro and in vivo.

Nature, 2014

Regeneration of skeletal muscle depends on a population of adult stem cells (satellite cells) tha... more Regeneration of skeletal muscle depends on a population of adult stem cells (satellite cells) that remain quiescent throughout life. Satellite cell regenerative functions decline with ageing. Here we report that geriatric satellite cells are incapable of maintaining their normal quiescent state in muscle homeostatic conditions, and that this irreversibly affects their intrinsic regenerative and self-renewal capacities. In geriatric mice, resting satellite cells lose reversible quiescence by switching to an irreversible pre-senescence state, caused by derepression of p16(INK4a) (also called Cdkn2a). On injury, these cells fail to activate and expand, undergoing accelerated entry into a full senescence state (geroconversion), even in a youthful environment. p16(INK4a) silencing in geriatric satellite cells restores quiescence and muscle regenerative functions. Our results demonstrate that maintenance of quiescence in adult life depends on the active repression of senescence pathways. As p16(INK4a) is dysregulated in human geriatric satellite cells, these findings provide the basis for stem-cell rejuvenation in sarcopenic muscles.

Journal of Experimental Medicine, 2011