Origins, Potency, and Heterogeneity of Skeletal Muscle Fibro-Adipogenic Progenitors—Time for New Definitions Osvaldo Contreras1,2,3* , Fabio M
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Contreras et al. Skeletal Muscle (2021) 11:16 https://doi.org/10.1186/s13395-021-00265-6 REVIEW Open Access Origins, potency, and heterogeneity of skeletal muscle fibro-adipogenic progenitors—time for new definitions Osvaldo Contreras1,2,3* , Fabio M. V. Rossi4 and Marine Theret4* Abstract Striated muscle is a highly plastic and regenerative organ that regulates body movement, temperature, and metabolism—all the functions needed for an individual’s health and well-being. The muscle connective tissue’s main components are the extracellular matrix and its resident stromal cells, which continuously reshape it in embryonic development, homeostasis, and regeneration. Fibro-adipogenic progenitors are enigmatic and transformative muscle-resident interstitial cells with mesenchymal stem/stromal cell properties. They act as cellular sentinels and physiological hubs for adult muscle homeostasis and regeneration by shaping the microenvironment by secreting a complex cocktail of extracellular matrix components, diffusible cytokines, ligands, and immune- modulatory factors. Fibro-adipogenic progenitors are the lineage precursors of specialized cells, including activated fibroblasts, adipocytes, and osteogenic cells after injury. Here, we discuss current research gaps, potential druggable developments, and outstanding questions about fibro-adipogenic progenitor origins, potency, and heterogeneity. Finally, we took advantage of recent advances in single-cell technologies combined with lineage tracing to unify the diversity of stromal fibro-adipogenic progenitors. Thus, this compelling review provides new cellular and molecular insights in comprehending the origins, definitions, markers, fate, and plasticity of murine and human fibro-adipogenic progenitors in muscle development, homeostasis, regeneration, and repair. Keywords: Mesenchymal stromal/stem cell, Fibro/adipogenic progenitor, Fibroblast, Adipocyte, Regeneration, Single-cell RNAseq Background Mammalian adult skeletal muscle has extraordinary re- In mammals, skeletal muscle represents ~ 30–40% of the generation capabilities upon injury, making the organ a total body mass, regulating body temperature, metabolism, perfect model to study regeneration and repair, and inves- and physical activity. Comprising the musculoskeletal sys- tigate the contribution of adult stem and interstitial cells tem, striated muscles are responsible for voluntary and in settings of acute or chronic injury. The muscle connect- non-voluntary movements. Skeletal muscles are recog- ive tissue (MCT) components are the extracellular matrix nized as highly plastic tissue, illustrated by atrophic or (ECM) and its stromal cells, which actively produce, main- hypertrophic changes when disused or trained. tain, and remodel this dynamic scaffold during develop- ment, homeostasis, and after trauma. * Correspondence: [email protected]; [email protected] Among the several cell types that participate in muscle re- 1Developmental and Stem Cell Biology Division, Victor Chang Cardiac generation, tissue-resident mesenchymal progenitors play a Research Institute, Darlinghurst, NSW 2010, Australia 4Biomedical Research Centre, Department of Medical Genetics and School of crucial role by providing signaling cues that modulate other Biomedical Engineering, University of British Columbia, Vancouver, BC V6T muscle-resident cells’ function, and actively remodel the 1Z3, Canada ECM during this process. Fibro-adipogenic progenitors Full list of author information is available at the end of the article © The Author(s). 2021 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Contreras et al. Skeletal Muscle (2021) 11:16 Page 2 of 25 (FAPs) have been identified as platelet-derived growth factor known as muscle fibroblasts [17–19]. However, com- receptor alpha (PDGFRα,alsoknownasPDGFRA)express- pared with the ever-growing knowledge about adult ing cells [1, 2].Agrowingbodyofevidenceshowsthat MCT, the composition and the dynamic remodeling of PDGFRα+ FAPs provide regenerative cues to control muscle embryonic MCT are poorly understood. While evidence stem cell (MuSC) expansion, fate, and myogenesis after acute about the ontogeny of interstitial muscle cells exists damage and aging [1–7]. Furthermore, the ablation of stro- [20–22], only a paucity of studies have reported their mal cells by using mice model expressing the diphtheria embryonic determination, and hence, the developmental toxin receptor (DTR) under the control of the fibroblast acti- origin and role of these ECM-embedded cells are not yet vation protein alpha promoter (FAPα-DTR) impairs the fully appreciated and understood. long-term maintenance of hematopoiesis, muscle mass, and Kardon and colleagues published early evidence of the cachexia [8]. To note, FAPα+ cells are found in most tissues function of these cells in the formation of limb muscles such as bone, salivary gland, visceral adipose tissue, skeletal in the 2000s [23]. The authors described that a mesoder- muscle, and pancreas; express CD90, CD140a, and SCA-1; mal population of TCF7L2+ cells (formerly known as T- and so are most likely to be mesenchymal progenitors, hence cell factor 4 or TCF-4, a TCF/LEF transcription factor FAPs in skeletal muscle [8]. These findings have been con- downstream the canonical Wnt/β-catenin signaling) reg- firmed by the Rando laboratory using a knock-in PDGFRαC- ulates the spatiotemporal determination and differenti- reER:Rosa26DTA mice model [7], and more recently, by ation of myogenic progenitors and, therefore, regulates Tsuchida’s group using a similar cell ablation strategy [9]. In- limb muscle development in chicks [23]. Limb TCF7L2+ deed, genetic ablation of PDGFRα+ lineage cells leads to im- precursors derive from the lateral plate mesoderm in a paired MuSC expansion and leucocyte infiltration, leading to muscle-specific pattern, but are different from myogenic deficient skeletal muscle regeneration after acute chemical precursors since they do not form muscle nor express injury and neuromuscular defects and muscle atrophy [7, 9]. classical myogenic markers (e.g., Pax7)[6, 23, 24]. Thus, In addition, following limb ischemia, proper muscle revascu- myogenic precursors are patterned by extrinsic cues, larization and repair are lost after ablating FAPs [10]. Hence, mostly coming from the MCT, after the cells have mi- PDGFRα+ FAPs are required for successful muscle regener- grated through the limb rather than being embryonically ation, repair, and maintenance during tissue homeostasis and predetermined to form particular muscle anatomical in pathological states. structures [23, 25]. These MCT progenitors also influ- Muscle-resident PDGFRα+ cells readily initiate fi- ence the myofiber type of limb and diaphragm muscles broblastic colonies (also called fibroblast colony- in a paracrine fashion [24]. Interestingly, not all limb formingunits,CFU-F,(Fig.1a)) and can clonally dif- muscles contain TCF7L2+ cells during mouse embryo ferentiate not only into activated fibroblasts/myofibro- development, which suggest a distinct patterning and blasts and adipocytes but also into chondrogenic and three-dimensional distribution of these cells in different osteogenic lineages depending on the context [1, 2, subtypes, or the existence of MCT progenitors that do 10–15]. The plasticity and clonal expansion of muscle not express this marker [26]. Nevertheless, TCF7L2 la- FAPs are also seen in humans [16]. However, the ef- bels a significant proportion of mammalian stromal non- fects of damage-induced signals and cues on their myogenic precursors at birth and during adulthood [24, plasticity, fate, and functions have only recently begun 27, 28]. Additionally, MuSCs and endothelial cells also to be explored. The development of new in vivo express Tcf7l2 mRNA and protein, albeit at low levels lineage tracing tools used to identify and track cells compared with FAPs [7, 24, 28]. expressing specific markers in various animal and Researchers have argued that vertebrate muscles de- damage models in parallel with the recent emergence rive from several developmental sources, adding com- of single-cell omics have allowed the identification of plexity to our understanding of the different origins of a broad spectrum of specific stromal populations and MCT in muscle development. For comprehensive re- their relative contribution to muscle homeostasis, re- views, see: [20–22]. Like myogenic precursors, MCT generation, and repair. progenitors originate from different and distinct struc- tural origins during