The underlying cause of aging remains one of the central mysteries of biology. Recent studies in several different systems suggest that not only may the rate of aging be modified by environmental and ...genetic factors, but also that the aging clock can be reversed, restoring characteristics of youthfulness to aged cells and tissues. This Review focuses on the emerging biology of rejuvenation through the lens of epigenetic reprogramming. By defining youthfulness and senescence as epigenetic states, a framework for asking new questions about the aging process emerges.
In vertebrates, activation of innate immunity is an early response to injury, implicating it in the regenerative process. However, the mechanisms by which innate signals might regulate stem cell ...functionality are unknown. Here, we demonstrate that type 2 innate immunity is required for regeneration of skeletal muscle after injury. Muscle damage results in rapid recruitment of eosinophils, which secrete IL-4 to activate the regenerative actions of muscle resident fibro/adipocyte progenitors (FAPs). In FAPs, IL-4/IL-13 signaling serves as a key switch to control their fate and functions. Activation of IL-4/IL-13 signaling promotes proliferation of FAPs to support myogenesis while inhibiting their differentiation into adipocytes. Surprisingly, type 2 cytokine signaling is also required in FAPs, but not in myeloid cells, for rapid clearance of necrotic debris, a process that is necessary for timely and complete regeneration of tissues.
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► Type 2 cytokine signaling via IL-4Rα is required for muscle regeneration ► Eosinophils secrete IL-4 and are required for regeneration of injured muscle ► Myeloid or satellite cell IL-4Rα signaling is dispensable for muscle regeneration ► IL-4Rα signaling regulates the functions of fibro/adipogenic progenitors in muscle
Muscle injury promotes recruitment of eosinophils, immune cells that provide a niche for proliferating stem cells in regenerating muscle. Secretion of IL-4 by eosinophils promotes proliferation of fibro/adipogenic progenitors (FAPs) while inhibiting their differentiation into adipocytes, facilitating the engulfment of necrotic debris by FAPs.
Stem cells and healthy aging Goodell, Margaret A.; Rando, Thomas A.
Science (American Association for the Advancement of Science),
12/2015, Letnik:
350, Številka:
6265
Journal Article
Recenzirano
Research into stem cells and aging aims to understand how stem cells maintain tissue health, what mechanisms ultimately lead to decline in stem cell function with age, and how the regenerative ...capacity of somatic stem cells can be enhanced to promote healthy aging. Here, we explore the effects of aging on stem cells in different tissues. Recent research has focused on the ways that genetic mutations, epigenetic changes, and the extrinsic environmental milieu influence stem cell functionality over time. We describe each of these three factors, the ways in which they interact, and how these interactions decrease stem cell health over time. We are optimistic that a better understanding of these changes will uncover potential strategies to enhance stem cell function and increase tissue resiliency into old age.
The exit of a stem cell out of quiescence into an activated state is characterized by major metabolic changes associated with increased biosynthesis of proteins and macromolecules. The regulation of ...this transition is poorly understood. Using muscle stem cells, or satellite cells (SCs), we found that autophagy, which catabolizes intracellular contents to maintain proteostasis and to produce energy during nutrient deprivation, was induced during SC activation. Inhibition of autophagy suppressed the increase in ATP levels and delayed SC activation, both of which could be partially rescued by exogenous pyruvate as an energy source, suggesting that autophagy may provide nutrients necessary to meet bioenergetic demands during this critical transition from quiescence to activation. We found that SIRT1, a known nutrient sensor, regulates autophagic flux in SC progeny. A deficiency of SIRT1 led to a delay in SC activation that could also be partially rescued by exogenous pyruvate. These studies suggest that autophagy, regulated by SIRT1, may play an important role during SC activation to meet the high bioenergetic demands of the activation process.
Synopsis
Tang and Rando report induction of autophagy by the nutrient sensor SIRT1 as crucial energy provider for efficient proliferation/differentiation in quiescent muscle satellite cells in vivo.
Muscle stem cells require autophagy to surmount a bioenergetic hurdle to break quiescence to enter an activated state.
Bioenergetic demands accompanying muscle stem cell activation induces autophagic flux.
These bioenergetic demands are signaled through SIRT1 to activate autophagy by interaction with ATG7 and through the AMPK pathway.
Tang and Rando report induction of autophagy by the nutrient sensor SIRT1 as crucial energy provider for efficient proliferation/differentiation in quiescent muscle satellite cells in vivo.
Most adult organs contain regenerative stem cells, often organized in specific niches. Stem cell function is critical for tissue homeostasis and repair upon injury, and it is dependent on ...interactions with the niche. During ageing, stem cells decline in their regenerative potential and ability to give rise to differentiated cells in the tissue, which is associated with a deterioration of tissue integrity and health. Ageing-associated changes in regenerative tissue regions include defects in maintenance of stem cell quiescence, differentiation ability and bias, clonal expansion and infiltration of immune cells in the niche. In this Review, we discuss cellular and molecular mechanisms underlying ageing in the regenerative regions of different tissues as well as potential rejuvenation strategies. We focus primarily on brain, muscle and blood tissues, but also provide examples from other tissues, such as skin and intestine. We describe the complex interactions between different cell types, non-cell-autonomous mechanisms between ageing niches and stem cells, and the influence of systemic factors. We also compare different interventions for the rejuvenation of old regenerative regions. Future outlooks in the field of stem cell ageing are discussed, including strategies to counter ageing and age-dependent disease.
Stem cell therapy for muscular dystrophies Biressi, Stefano; Filareto, Antonio; Rando, Thomas A
The Journal of clinical investigation,
11/2020, Letnik:
130, Številka:
11
Journal Article
Recenzirano
Odprti dostop
Muscular dystrophies are a heterogeneous group of genetic diseases, characterized by progressive degeneration of skeletal and cardiac muscle. Despite the intense investigation of different ...therapeutic options, a definitive treatment has not been developed for this debilitating class of pathologies. Cell-based therapies in muscular dystrophies have been pursued experimentally for the last three decades. Several cell types with different characteristics and tissues of origin, including myogenic stem and progenitor cells, stromal cells, and pluripotent stem cells, have been investigated over the years and have recently entered in the clinical arena with mixed results. In this Review, we do a roundup of the past attempts and describe the updated status of cell-based therapies aimed at counteracting the skeletal and cardiac myopathy present in dystrophic patients. We present current challenges, summarize recent progress, and make recommendations for future research and clinical trials.
Adult stem cells are important for mammalian tissues, where they act as a cell reserve that supports normal tissue turnover and can mount a regenerative response following acute injuries. Quiescent ...stem cells are well established in certain tissues, such as skeletal muscle, brain, and bone marrow. The quiescent state is actively controlled and is essential for long-term maintenance of stem cell pools. In this Review, we discuss the importance of maintaining a functional pool of quiescent adult stem cells, including haematopoietic stem cells, skeletal muscle stem cells, neural stem cells, hair follicle stem cells, and mesenchymal stem cells such as fibro-adipogenic progenitors, to ensure tissue maintenance and repair. We discuss the molecular mechanisms that regulate the entry into, maintenance of, and exit from the quiescent state in mice. Recent studies revealed that quiescent stem cells have a discordance between RNA and protein levels, indicating the importance of post-transcriptional mechanisms, such as alternative polyadenylation, alternative splicing, and translation repression, in the control of stem cell quiescence. Understanding how these mechanisms guide stem cell function during homeostasis and regeneration has important implications for regenerative medicine.
Skeletal muscle has an extraordinary regenerative capacity due to the activity of tissue-specific muscle stem cells. Consequently, these cells have received the most attention in studies ...investigating the cellular processes of skeletal muscle regeneration. However, efficient capacity to rebuild this tissue also depends on additional cells in the local milieu, as disrupting their normal contributions often leads to incomplete regeneration. Here, we review these additional cells that contribute to the regenerative process. Understanding the complex interactions between and among these cell populations has the potential to lead to therapies that will help promote normal skeletal muscle regeneration under conditions in which this process is suboptimal.
Wosczyna and Rando present a Review of the complex cellular milieu surrounding regenerating muscle. They describe the cell types themselves, as well as how they contribute to the regulation of muscle stem cells in the regeneration process.
Adult stem cells exist in most mammalian organs and tissues and are indispensable for normal tissue homeostasis and repair. In most tissues, there is an age-related decline in stem cell functionality ...but not a depletion of stem cells. Such functional changes reflect deleterious effects of age on the genome, epigenome, and proteome, some of which arise cell autonomously and others of which are imposed by an age-related change in the local milieu or systemic environment. Notably, some of the changes, particularly epigenomic and proteomic, are potentially reversible, and both environmental and genetic interventions can result in the rejuvenation of aged stem cells. Such findings have profound implications for the stem cell-based therapy of age-related diseases.
Severe traumatic skeletal muscle injuries, such as volumetric muscle loss (VML), result in the obliteration of large amounts of skeletal muscle and lead to permanent functional impairment. Current ...clinical treatments are limited in their capacity to regenerate damaged muscle and restore tissue function, promoting the need for novel muscle regeneration strategies. Advances in tissue engineering, including cell therapy, scaffold design, and bioactive factor delivery, are promising solutions for VML therapy. Herein, we review tissue engineering strategies for regeneration of skeletal muscle, development of vasculature and nerve within the damaged muscle, and achievements in immunomodulation following VML. In addition, we discuss the limitations of current state of the art technologies and perspectives of tissue-engineered bioconstructs for muscle regeneration and functional recovery following VML.
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