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Trends in Cell Biology
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The emergence of the stem cell niche

Open AccessPublished:August 04, 2022DOI:https://doi.org/10.1016/j.tcb.2022.07.003

      Highlights

      • Niches coevolve with the maturation of progenitor and stem cells from development through to adulthood.
      • Fetal progenitors in emerging niches are highly expansive, whereas adult niches regulate stem cell quiescence.
      • Fetal progenitors are less able to occupy adult niches during transplantation.
      • Niche formation is stepwise, involving cell–cell contact, followed by cell–extracellular matrix contact, to affect cell polarity and maturation.
      • Emerging niches use similar pathways and mechanisms during regeneration.
      • Understanding niche formation may improve the quality and quantity of stem cells within niches.
      • Supportive cell types in emerging niches are different from homeostatic adult niches.
      • Human pluripotent stem cell lineages can be used to model components of niche development in vitro and in vivo.
      Stem cell niches are composed of dynamic microenvironments that support stem cells over a lifetime. The emerging niche is distinct from the adult because its main role is to support the progenitors that build organ systems in development. Emerging niches mature through distinct stages to form the adult niche and enable proper stem cell support. As a model of emerging niches, this review highlights how differences in the skeletal muscle microenvironment influence emerging versus satellite cell (SC) niche formation in skeletal muscle, which is among the most regenerative tissue systems. We contrast how stem cell niches regulate intrinsic properties between progenitor and stem cells throughout development to adulthood. We describe new applications for generating emerging niches from human pluripotent stem cells (hPSCs) using developmental principles and highlight potential applications for regeneration and therapeutics.

      Keywords

      Introduction

      Precise control over stem cell self-renewal and differentiation is essential for proper organogenesis and tissue homeostasis. Immediately juxtaposed to stem cells are specialized microenvironments, termed ‘niches’, containing multiple cell types guiding stem cell behavior. Just as adult stem cells are dynamically regulated by their niche, embryonic niches formed in development equivalently control cell fate decisions to mature from an early precursor or progenitor and eventually to an adult quiescent stem cell. Importantly, embryonic niches also change over these developmental contexts. This review seeks to identify how changes during development in both the stem cell and its niche affect behavior and characteristics of one another. We examine the idea of the emerging niche, defined as initial niches in development that help to capture or support fetal progenitor cells and direct their proliferative nature and eventual generation of quiescent adult stem cells. We specifically focus on niche emergence in skeletal muscle, but we highlight universal themes in emerging niche biology broadly across multiple stem cell systems and compare these with adult niches.

      Overview and importance of emerging stem cell niches in multiple systems

      The initial niches formed in development are likely the most regenerative and pristine but may evolve over a lifespan or become altered in disease. Niches across tissue systems share common features, such as regulating progenitor to adult cell maturation, self-renewal, and activation states during regeneration.
      A common theme for many niche systems is supporting waves of developing progenitors and stem cells. One of the best understood emerging niche systems is the hematopoietic stem cell (HSC) niche, which supports two HSC waves that give rise to all blood cells. The first primitive hematopoiesis wave produces transient hematopoietic cells to meet the immediate needs of the embryo, including primitive erythroid progenitors required for oxygenation. Definitive hematopoiesis then generates HSCs that give rise to all mature blood cells and have long-term repopulation potential.
      Hematopoiesis occurs in discrete anatomical niches, including from the aorta-gonad-mesonephros region, arteries, yolk sac, and placenta, that are age-matched for appropriate maturation and lineage specification [
      • Rhodes K.E.
      • et al.
      The emergence of hematopoietic stem cells is initiated in the placental vasculature in the absence of circulation.
      ,
      • Gao X.
      • et al.
      The hematopoietic stem cell niche: from embryo to adult.
      ]. Fetal HSCs seed the fetal liver, expand, and migrate to the adult niche in the bone marrow stroma, where they reside throughout adult life and become predominantly quiescent. As fetal HSCs mature, they begin to express receptors, including integrin-αM and GPI-80, that support migration from the liver and interaction with the stromal niche [
      • Prashad S.L.
      • et al.
      GPI-80 defines self-renewal ability in hematopoietic stem cells during human development.
      ]. Interestingly, some definitive HSCs that originate from distinct fetal niches cease to persist into adulthood and instead are the cell of origin for tissue-resident innate-like lymphocytes [
      • Beaudin A.E.
      • et al.
      A transient developmental hematopoietic stem cell gives rise to innate-like B and T cells.
      ]. In HSCs, the emerging niche is key for preventing alternate fate specification, such as to a cardiomyogenic fate [
      • Van Handel B.
      • et al.
      Scl represses cardiomyogenesis in prospective hemogenic endothelium and endocardium.
      ]. The generation and maturation processes of HSCs during embryonic and neonatal development are primarily stimulated by inflammatory cytokines, which change over time, and there is still much debate on the role of intrinsic and extrinsic regulation of true HSC potential in the niche.
      Interestingly, another common theme for many adult niche systems is reversion toward the developmental-like niche after an injury to support stem cell regeneration. The brain houses at least two well-studied neural stem cell (NSC) niches in the subgranular zone in the hippocampal dentate gyrus and the subventricular zone around the lateral ventricles [
      • Fuentealba L.C.
      • et al.
      Embryonic origin of postnatal neural stem cells.
      ,
      • Miller F.D.
      • Gauthier-Fisher A.
      Home at last: neural stem cell niches defined.
      ]. A recent study performed single-cell profiling plus lineage tracing of mouse forebrain NSCs and showed that dormant NSCs reacquire developmental-like states when activated to generate adult-born neurons [
      • Borrett M.J.
      • et al.
      Single-cell profiling shows murine forebrain neural stem cells reacquire a developmental state when activated for adult neurogenesis.
      ]. Notably, almost half of all transcriptomic differences were involved in regulating and/or sensing the niche environment, including cues from neurotransmitters, receptor ligands, and extracellular matrix (ECM) proteoglycans. Bidirectional switches between activated and dormant states during brain development or regeneration may be determined by the niche environment, including proper vascular formation, ECM, and supportive niche cells such as microglia that secrete neurogenic factors.

      The making of the stem cell niche in skeletal muscle

      The adult skeletal muscle SC niche is a precise anatomical location between the plasma membrane of myofibers and a laminin-rich basal lamina. In contrast, emerging niches of skeletal muscle loosely consist of minimal basal lamina and immature myofibers that enable progenitor expansion of the rapidly growing muscle [
      • Sambasivan R.
      • Tajbakhsh S.
      Skeletal muscle stem cell birth and properties.
      ,
      • Buckingham M.
      • et al.
      The formation of skeletal muscle: from somite to limb.
      ].
      Skeletal muscle precursor/progenitor cells (SMPCs) in trunk and limb originate through segmentation of the paraxial mesoderm, leading to somitogenesis, which results in the formation of distinct anterior/posterior compartments important for specification of the dermomyotome and myotome structures that produce embryonic SMPCs. Key components of the dermomyotome and myotome niches, including signals from the emerging neural tube/ectoderm and mesenchyme, are reviewed elsewhere [
      • Buckingham M.
      • et al.
      The formation of skeletal muscle: from somite to limb.
      ].
      Once embryonic progenitor cells emerge from the myotome, one of the first steps in the formation of the niche is cell–cell adhesion between SMPCs and the sarcolemma of newly formed myofibers through interactions with M- and N-cadherins and CD82 [
      • Goel A.J.
      • et al.
      Niche cadherins control the quiescence-to-activation transition in muscle stem cells.
      ,
      • Alexander M.S.
      • et al.
      CD82 is a marker for prospective isolation of human muscle satellite cells and is linked to muscular dystrophies.
      ]. This interaction occurs prior to the formation of the basal lamina (M.R. Hicks et al., unpublished). As multiple myofibers aggregate to form myobundles, a subset of progenitors become encompassed by fusing myofibers, noted by spectrin-positive cross-bridges [
      • Duan R.
      • et al.
      Spectrin is a mechanoresponsive protein shaping fusogenic synapse architecture during myoblast fusion.
      ] (Figure 1). Between human fetal weeks 11–13 (approximately embryonic day e14 in mouse), myofibers begin to express basal lamina such as laminin-211 that ensheathes the myobundles and associated progenitors to form the fetal niche [
      • Brohl D.
      • et al.
      Colonization of the satellite cell niche by skeletal muscle progenitor cells depends on Notch signals.
      ,
      • Rayagiri S.S.
      • et al.
      Basal lamina remodeling at the skeletal muscle stem cell niche mediates stem cell self-renewal.
      ].
      Figure 1
      Figure 1The emerging fetal and adult skeletal muscle niche.
      Shown is an example of differences between (A) fetal skeletal muscle precursor/progenitor cells (SMPCs) at the beginning of secondary myogenesis and (B) adult skeletal muscle satellite cells (SCs) within their niche and microenvironment [
      • Xi H.
      • et al.
      A human skeletal muscle atlas identifies the trajectories of stem and progenitor cells across development and from human pluripotent stem cells.
      ]. Multiple SMPCs in the emerging niche illustrate increased number or set point. SMPCs adhere to clusters of small secondary myofibers termed ‘myobundles’, and SCs reside at the periphery of large adult myofibers with a laminin-rich basal lamina. In contrast, SMPCs produce high levels of extracellular matrix proteins and are in direct contact with multiple nonmyogenic cell types that are unique from the adult niche.
      Fetal SMPCs produce an order of magnitude greater level of ECM than adult SCs, which contributes to autonomous niche building [
      • Tierney M.T.
      • et al.
      Autonomous extracellular matrix remodeling controls a progressive adaptation in muscle stem cell regenerative capacity during development.
      ]. The fetal niche includes fibronectin, collagens, nidogens, matrix metalloproteases, tenascin C, and others that provide scaffolding for fetal SMPCs and also serve as a reservoir for growth factors such as insulin-like growth factor 1 and transforming growth factor-β superfamily members to promote fetal muscle hypertrophy [
      • Gonzalez A.M.
      • et al.
      Distribution of fibroblast growth factor (FGF)-2 and FGF receptor-1 messenger RNA expression and protein presence in the mid-trimester human fetus.
      ,
      • Hannon K.
      • et al.
      Differentially expressed fibroblast growth factors regulate skeletal muscle development through autocrine and paracrine mechanisms.
      ] and fibroblast growth factors (FGFs) essential to SMPC expansion [
      • McPherron A.C.
      • et al.
      Regulation of skeletal muscle mass in mice by a new TGF-β superfamily member.
      ,
      • Liu J.P.
      • et al.
      Mice carrying null mutations of the genes encoding insulin-like growth factor I (Igf-1) and type 1 IGF receptor (Igf1r).
      ,
      • Gonzalez A.M.
      • et al.
      Distribution of fibroblast growth factor (FGF)-2 and FGF receptor-1 messenger RNA expression and protein presence in the mid-trimester human fetus.
      ,
      • Hannon K.
      • et al.
      Differentially expressed fibroblast growth factors regulate skeletal muscle development through autocrine and paracrine mechanisms.
      ]. The composition of fetal ECM differs from the adult niche, which includes embryonic laminin isoforms LAMA511 and LAMA111, which may facilitate formation of new myofibers [
      • Rayagiri S.S.
      • et al.
      Basal lamina remodeling at the skeletal muscle stem cell niche mediates stem cell self-renewal.
      ,
      • Penton C.M.
      • et al.
      Laminin 521 maintains differentiation potential of mouse and human satellite cell-derived myoblasts during long-term culture expansion.
      ]. ECM composition also influences niche stiffness, allowing loose association of the SMPCs to the myofibers through multiple binding sites, including fetal integrins such as integrin-α6 [
      • Goody M.F.
      • et al.
      NAD+ biosynthesis ameliorates a zebrafish model of muscular dystrophy.
      ], and potentially regulates lineage commitment through YAP/TAZ signaling.
      Over development, the skeletal muscle dynamically changes to support three waves of myogenesis in part by tendon connections that apply tensile forces [
      • Kardon G.
      Muscle and tendon morphogenesis in the avian hind limb.
      ] and motor neuron innervation leading to contraction [
      • Lin W.
      • et al.
      Distinct roles of nerve and muscle in postsynaptic differentiation of the neuromuscular synapse.
      ] and structural maturation of the myofiber. The first primary skeletal muscles arise in the limb from e10.5 to e12 in the mouse [
      • Lyons G.E.
      • et al.
      The expression of myosin genes in developing skeletal muscle in the mouse embryo.
      ] or weeks 6–9 in humans [
      • Xi H.
      • et al.
      A human skeletal muscle atlas identifies the trajectories of stem and progenitor cells across development and from human pluripotent stem cells.
      ] to establish basic muscle patterning and are usually considered to be slow-twitch fibers marked by embryonic MYH3 [
      • Sacks L.D.
      • et al.
      Regulation of myosin expression during myotome formation.
      ]. Primary myofibers support adjacent progenitors in the limb that express PAX3 and the transition to early PAX7 progenitors [
      • Relaix F.
      • et al.
      A Pax3/Pax7-dependent population of skeletal muscle progenitor cells.
      ]. Motor neurons emerge from the ectoderm in weeks 6–9 in the human limb [
      • Shinohara H.
      • et al.
      Development of the innervation pattern in the upper limb of staged human embryos.
      ] and continue to mature and innervate in concert with the formation of secondary fetal myofibers. Secondary myofibers transition to fast-twitch fibers characterized by fetal myosin MYH8 and fetal actin ACTC1 that support the rapid expansion of fetal PAX7+ SMPCs and contribute to growing muscle. Secondary myogenesis is thought to occur around e12–e16 in mouse limbs and corresponds with innervation in humans by weeks 9–11 [
      • Hesselmans L.F.
      • et al.
      Development of innervation of skeletal muscle fibers in man: relation to acetylcholine receptors.
      ,
      • Sanes J.R.
      • Lichtman J.W.
      Development of the vertebrate neuromuscular junction.
      ], but timing may vary depending on anatomical location. Secondary myofibers are initially polyinnervated and express fetal acetylcholine subunits, but this begins to decrease at fetal week 16 in humans [
      • Hesselmans L.F.
      • et al.
      Development of innervation of skeletal muscle fibers in man: relation to acetylcholine receptors.
      ]. Interestingly, fetal acetylcholine receptors are re-expressed during regeneration throughout adult muscle [
      • Cetin H.
      • et al.
      The structure, function, and physiology of the fetal and adult acetylcholine receptor in muscle.
      ], similar to what is seen in other niche systems. Structural maturation of fetal myofibers corresponds with changes to their plasma membrane, including expression of potassium-gated ion channels and calcium channels such as Piezo1 that regulate sarcolemma phospholipids and begin to assemble the components needed to build the SC niche [
      • Ma N.
      • et al.
      Piezo1 regulates the regenerative capacity of skeletal muscles via orchestration of stem cell morphological states.
      ,
      • Tsuchiya M.
      • et al.
      Cell surface flip-flop of phosphatidylserine is critical for PIEZO1-mediated myotube formation.
      ]. Adult myofibers of the limb are made up of multiple myosins, which include MYH1 and MYH2, unless they are undergoing regeneration, in which case they re-express embryonic and fetal myosin isoforms, such as what is seen in emerging niches in development.

      Microenvironment of emerging niches

      Emerging niches are also composed of several nonmyogenic cell types in the developing limb that are nearby or in contact with SMPCs (Figure 1). Prominent cell populations include preosteogenic SHOX2+ progenitors and prechondrogenic SOX9+ progenitors involved in bone or cartilage formation, respectively [
      • Xi H.
      • et al.
      A human skeletal muscle atlas identifies the trajectories of stem and progenitor cells across development and from human pluripotent stem cells.
      ,
      • Skuplik I.
      • et al.
      Identification of a limb enhancer that is removed by pathogenic deletions downstream of the SHOX gene.
      ]. SHOX2-deficient limbs have aberrant neural and muscle formation during forelimb development [
      • Vickerman L.
      • et al.
      Shox2 function couples neural, muscular and skeletal development in the proximal forelimb.
      ]. The developing microenvironment also contains mesenchymal DUSP6+ progenitors that provide key morphogens needed for support and lineage specification of skeletal muscle [
      • Huang A.H.
      Coordinated development of the limb musculoskeletal system: tendon and muscle patterning and integration with the skeleton.
      ,
      • Engler A.J.
      • et al.
      Matrix elasticity directs stem cell lineage specification.
      ]. DUSP6+ progenitors are multipotent but become more lineage restricted overtime, forming dermal TWIST2+ fibroblasts of the fascia, tenogenic TNMD+ cells that subdivide muscle masses [
      • Kardon G.
      Muscle and tendon morphogenesis in the avian hind limb.
      ], and fetal CD73+ stromal cells that differentially remodel the emerging niche. Fetal stromal cells coexpress platelet-derived growth factor receptor-α (PDGFRα), a marker for adult fibroadipogenic progenitors (FAPs), which are important support cells during adult SC regeneration [
      • Joe A.W.B.
      • et al.
      Muscle injury activates resident fibro/adipogenic progenitors that facilitate myogenesis.
      ,
      • Uezumi A.
      • et al.
      Mesenchymal progenitors distinct from satellite cells contribute to ectopic fat cell formation in skeletal muscle.
      ]. However, fetal stromal cells differ from adult FAPs, including by increased hepatocyte growth factor and reduced interleukin-6 (IL-6) secretion, which regulate migration and expansion of SMPCs [
      • Kim J.Y.
      • et al.
      Twist2-driven chromatin remodeling governs the postnatal maturation of dermal fibroblasts.
      ]. Also abundant in human fetal muscles are AIF1-expressing hematopoietic lineages that may give rise to tissue-resident macrophages [
      • Xi H.
      • et al.
      A human skeletal muscle atlas identifies the trajectories of stem and progenitor cells across development and from human pluripotent stem cells.
      ]. Macrophage subtypes regulate SMPC activation, clearance of cellular debris, tissue immune surveillance, and the resolution of inflammation [
      • Arnold L.
      • et al.
      Inflammatory monocytes recruited after skeletal muscle injury switch into antiinflammatory macrophages to support myogenesis.
      ]. Model organisms have demonstrated that macrophages provide a transient muscle stem cell niche via nicotinamide phosphoribosyltransferase secretion during regeneration [
      • Ratnayake D.
      • et al.
      Macrophages provide a transient muscle stem cell niche via NAMPT secretion.
      ]. Table 1 provides a summary of emerging niche populations.
      Table 1Supportive cell types in the emerging niche.
      Abbreviations: BMP, bone morphogenetic protein; ECM, extracellular matrix; SMPC, skeletal muscle precursor/progenitor cell.
      Cell populations in the emerging nicheMarkersPotential roles in emerging niche formation
      Fetal myofibersMYH8, ACTC1, spectrinAdhesion to fetal SMPCs, building of ECM needed to support SMPCs
      PrechondrocyteSOX5, SOX6, SOX9Specification and support of muscle development, BMP production
      PreosteoblastSHOX2Specification and support of muscle [
      • Vickerman L.
      • et al.
      Shox2 function couples neural, muscular and skeletal development in the proximal forelimb.
      ]
      Limb mesenchymeDUSP6Wnt regulation and limb formation
      Tendon precursorsSOX9, TNMD, SCXSkeletal muscle patterning and tensile forces inducing structural maturation [
      • Kardon G.
      Muscle and tendon morphogenesis in the avian hind limb.
      ,
      • Huang A.H.
      Coordinated development of the limb musculoskeletal system: tendon and muscle patterning and integration with the skeleton.
      ]
      Dermal fibroblastsTWIST2, KRT19Chromatin remodeling and maturation [
      • Kim J.Y.
      • et al.
      Twist2-driven chromatin remodeling governs the postnatal maturation of dermal fibroblasts.
      ], formation of the fascia
      Stromal cellsCD73, PDGFRαRegulation of immune system and SMPC activation through cytokine section and adipocyte versus fibrotic differentiation [
      • Heredia J.E.
      • et al.
      Type 2 innate signals stimulate fibro/adipogenic progenitors to facilitate muscle regeneration.
      ]
      Neural crestSOX10, Wnt1Prevention of premature differentiation of fetal SMPCs [
      • Van Ho A.T.
      • et al.
      Neural crest cell lineage restricts skeletal muscle progenitor cell differentiation through Neuregulin1-ErbB3 signaling.
      ]
      Schwann cellsCDH19Neuromuscular junction formation and maintenance [
      • Barik A.
      • et al.
      Schwann cells in neuromuscular junction formation and maintenance.
      ]
      Vascular and endothelial cellsESAM, APMetabolite and growth factor support to the skeletal muscle [
      • Zhang J.
      • et al.
      Endothelial lactate controls muscle regeneration from ischemia by inducing M2-like macrophage polarization.
      ]
      MacrophagesSRGN, AIF1Regulates muscle regeneration, stromal cell activation and maturation
      a Abbreviations: BMP, bone morphogenetic protein; ECM, extracellular matrix; SMPC, skeletal muscle precursor/progenitor cell.

      Niche support of intrinsic differences between progenitor and stem cell states

      Fetal progenitors and adult stem cells have key intrinsic differences that are tightly regulated by their niches. In skeletal muscle, both SMPCs and SCs express the quintessential transcription factor PAX7, but many other myogenic regulatory factors and signaling are markedly different. Adult SCs have tightly controlled transitions between quiescent and activated states that are PAX7+MYF5− or PAX7+MYF5+ [
      • Kuang S.
      • et al.
      Asymmetric self-renewal and commitment of satellite stem cells in muscle.
      ]. When adult SCs express MYOD, they readily and robustly differentiate to myofibers. Unlike adult SCs, fetal PAX7+ SMPCs coexpress myogenic regulatory factors MYF5 and MYOD without differentiating into myofibers and are maintained in an activated state for extended periods of time, enabling expansion of the progenitor pool in vivo until the niche matures [
      • Buckingham M.
      • Rigby P.W.
      Gene regulatory networks and transcriptional mechanisms that control myogenesis.
      ].

      Niche-regulated proliferation

      One of the most striking differences in the fetal niche is the presence of amplifying progenitors in S/G2/M phases [
      • Esteves de Lima J.
      • et al.
      Specific pattern of cell cycle during limb fetal myogenesis.
      ]. Progenitors are marked by high levels of EdU and Ki67 during limb development and at myotendinous junctions. Coinciding with proliferative differences, the fetal niche supports progenitors at densities 100-fold greater than the adult niche. Proliferative demands are reflected in SMPC metabolism, which is highly glycolytic and has mitochondrial respiratory capacity more similar to activated adult SCs after injury. The fetal niche tightly regulates low oxygen levels through hypoxia-inducible factor-1α and is used to drive proliferation and muscle mass [
      • Majmundar A.J.
      • et al.
      HIF modulation of Wnt signaling regulates skeletal myogenesis in vivo.
      ]. Skeletal muscle growth is also particularly vulnerable in the fetus exposed to undernutrition from placental insufficiency. In contrast, adult SCs primarily metabolize through oxidative phosphorylation [
      • Xi H.
      • et al.
      A human skeletal muscle atlas identifies the trajectories of stem and progenitor cells across development and from human pluripotent stem cells.
      ,
      • Pala F.
      • et al.
      Distinct metabolic states govern skeletal muscle stem cell fates during prenatal and postnatal myogenesis.
      ]. Adult stem cells maintain the quiescent G0 state for extended periods of time, although a limited number of SCs fuse with adult myofibers to maintain homeostasis [
      • Pawlikowski B.
      • et al.
      Pervasive satellite cell contribution to uninjured adult muscle fibers.
      ]. Cell stress regulation induced by the niche is a key feature of quiescence that is required to prevent replication-associated mutations [
      • Salvi J.S.
      • et al.
      ATR activity controls stem cell quiescence via the cyclin F-SCF complex.
      ]. Key cellular responses to DNA damage pathway modulators, p53 and p16, have been shown to control quiescence across many adult stem cell systems not seen in fetal progenitors [
      • Liu Y.
      • et al.
      p53 regulates hematopoietic stem cell quiescence.
      ].

      Niche signaling

      Signaling pathways that regulate the interaction of the myofiber with progenitor or stem cells are key components helping to regulate the sequential colonization of the niche (Figure 2). Among the best-defined niche signals is the highly conserved Notch signaling system, which transduces short-range signals by interacting with transmembrane ligands such as Delta (DLL1) and Jagged-1 on neighboring cells [
      • Brack A.S.
      • et al.
      A temporal switch from notch to Wnt signaling in muscle stem cells is necessary for normal adult myogenesis.
      ]. While Notch signaling is a shared pathway between both SMPCs and SCs, Notch may interact with different coreceptors to induce niche colonization by SMPCs or maintain quiescence by SCs. Emerging SCs are driven into the interstitial space by a lack of Notch signals which is mediated through Rpbj. Mislocated SCs do not contribute to normal fiber growth in fetal development [
      • Brohl D.
      • et al.
      Colonization of the satellite cell niche by skeletal muscle progenitor cells depends on Notch signals.
      ]. Another important signaling pathway are the integrins that interact with fetal and adult laminin isoforms that form the basal lamina of the niche. Integrin-α6 interacts with fetal laminin-111 and stimulates regeneration [
      • Goody M.F.
      • et al.
      NAD+ biosynthesis ameliorates a zebrafish model of muscular dystrophy.
      ], whereas integrin-α7 and -β1 interact with adult laminin-211 but not embryonic isoforms [
      • von der Mark H.
      • et al.
      Alternative splice variants of α7β1 integrin selectively recognize different laminin isoforms.
      ] and are involved in several downstream signaling cascades, including focal adhesion kinases, cytoskeletal rearrangement, and RhoA [
      • Costa P.
      • et al.
      Integrin-specific control of focal adhesion kinase and RhoA regulates membrane protrusion and invasion.
      ], which regulates the quiescent state.
      Figure 2
      Figure 2Intrinsic differences in skeletal muscle precursor/progenitor cells (SMPCs) and satellite cells (SCs).
      Cartoon depicts key differences in niche-derived signaling pathways identified between (A) SMPCs and (B) SCs. These ligands and receptors present on stem cells, or their niche cells, may influence cell behavior that includes proliferation, maturation, and quiescence.

      Niche engulfment

      As fetal myofibers undergo hypertrophy and fusion, the SMPCs adhered to the myofibers’ periphery become ‘engulfed’ by the niche. A multitude of receptors promote adhesion sites between fetal SMPCs and myofibers; these include M-cadherin, Mcam, Megf10, several α-integrins, and Vcam-1 [
      • Brohl D.
      • et al.
      Colonization of the satellite cell niche by skeletal muscle progenitor cells depends on Notch signals.
      ,
      • Hughes S.M.
      • Blau H.M.
      Migration of myoblasts across basal lamina during skeletal muscle development.
      ,
      • Lapan A.D.
      • et al.
      Human fetal skeletal muscle contains a myogenic side population that expresses the melanoma cell-adhesion molecule.
      ]. Of these, Megf10 is an epidermal growth factor (EGF) repeat-containing transmembrane protein that is known for functioning as an engulfment receptor across tissues that can lead to actin polymerization [
      • Hamon Y.
      • et al.
      Cooperation between engulfment receptors: the case of ABCA1 and MEGF10.
      ] and, when overexpressed, can lead to cell engulfment of other cell types [
      • Scheib J.L.
      • et al.
      Jedi-1 and MEGF10 signal engulfment of apoptotic neurons through the tyrosine kinase Syk.
      ]. Megf10 is highly expressed in SMPCs and interacts with Notch and integrins, and Megf10 knockout mice have impaired muscle regeneration [
      • Saha M.
      • et al.
      Consequences of MEGF10 deficiency on myoblast function and Notch1 interactions.
      ], which may in part be due to Megf10’s importance for SMPC engulfment into the niche.

      Niche-regulated cell polarity

      Acquisition of cell polarity is an important parameter of stem cell maturation for many tissues, including the hair follicle, blood, nervous system, and skeletal muscle [
      • Castanieto A.
      • et al.
      EGFR signaling promotes self-renewal through the establishment of cell polarity in Drosophila follicle stem cells.
      ]. In HSCs, loss of the key polarity protein Lis1 prevents blood formation, resulting in embryonic lethality, and impairment of cell polarity in NSCs is linked to neurodevelopmental disorders such as Down syndrome, fragile X syndrome, autism spectrum disorder, and schizophrenia [
      • Arai Y.
      • Taverna E.
      Neural progenitor cell polarity and cortical development.
      ]. In the adult, when polarity goes awry, HSCs accelerate differentiation, which, in this context, prevents their ability to transform to myeloid leukemia by regulating inheritance of cell fate determinants [
      • Zimdahl B.
      • et al.
      Lis1 regulates asymmetric division in hematopoietic stem cells and in leukemia.
      ].
      Upon formation of the skeletal muscle niche, cells begin to establish an apical and a basal side, which enables polarity and asymmetric divisions of SCs both to form myoblasts and to self-renew. In contrast, fetal SMPCs are more prone to symmetrically divide [
      • Evano B.
      • et al.
      Dynamics of asymmetric and symmetric divisions of muscle stem cells in vivo and on artificial niches.
      ]. Through an in vitro muscle stem cell niche screen, epidermal growth factor receptor (EGFR) and Aurora kinase pathways were identified as key determinants of SC polarity through peroxisome proliferator-activated receptor-γ and CARM1 [
      • Wang Y.X.
      • et al.
      EGFR-Aurka signaling rescues polarity and regeneration defects in dystrophin-deficient muscle stem cells by increasing asymmetric divisions.
      ]. In contrast, early fetal SMPCs do not express EGFR but highly express other family members of the EGFR pathway, such as ERBB3, which is shown to promote SMPC expansion and survival. ERBB3 is not expressed by adult SCs unless activated [
      • Figeac N.
      • et al.
      ErbB3 binding protein-1 (Ebp1) controls proliferation and myogenic differentiation of muscle stem cells.
      ]. ERBB family members dimerize to affect downstream signaling, and the divergent expression between ERBB3 and EGFR and cosignaling pathways may represent a key transitory period between activation and quiescence states [
      • Golding J.P.
      • et al.
      Skeletal muscle stem cells express anti-apoptotic ErbB receptors during activation from quiescence.
      ]. Indeed, as SCs are displaced from their niche, EGFR is among the first receptors to reduce expression [
      • Wang Y.X.
      • et al.
      EGFR-Aurka signaling rescues polarity and regeneration defects in dystrophin-deficient muscle stem cells by increasing asymmetric divisions.
      ].

      Niche receptors of SC quiescence

      The calcitonin receptor (Calcr) is uniquely expressed by quiescent adult SCs and inhibits SCs from escaping the SC niche [
      • Yamaguchi M.
      • et al.
      Calcitonin receptor signaling inhibits muscle stem cells from escaping the quiescent state and the niche.
      ]. The Notch-COLV-Calcr signaling cascade maintains SCs in a quiescent state in a cell-autonomous fashion [
      • Baghdadi M.B.
      • et al.
      Reciprocal signalling by Notch-collagen V-CALCR retains muscle stem cells in their niche.
      ] that is thought to occur in mouse by 2 weeks postnatally [
      • Gattazzo F.
      • et al.
      Distinct phases of postnatal skeletal muscle growth govern the progressive establishment of muscle stem cell quiescence.
      ]. Oncostatin M (OSM) receptor is a member of the IL-6 family and another important receptor of adult SCs. OSM is expressed by nascent myofibers in the niche 4–10 days after injury and is a potent molecule for reinduction of SC quiescence [
      • Sampath S.C.
      • et al.
      Induction of muscle stem cell quiescence by the secreted niche factor oncostatin M.
      ]. OSM stimulates the Stat3 pathway, which is among the most potent drivers of adult SC quiescence [
      • Tierney M.T.
      • et al.
      STAT3 signaling controls satellite cell expansion and skeletal muscle repair.
      ] and is weakly expressed or not expressed at all in fetal SMPCs.

      Stem cell niches regulate functional potential

      In mouse, a single adult SC transplanted into a recipient muscle can self-renew to form many myofibers and re-establish the stem cell pool [
      • Sacco A.
      • et al.
      Self-renewal and expansion of single transplanted muscle stem cells.
      ] and can be serially transplanted into multiple recipients with continued stemness [
      • Rocheteau P.
      • et al.
      A subpopulation of adult skeletal muscle stem cells retains all template DNA strands after cell division.
      ]. This is the gold standard test for stem cells, as is shown in multiple stem cell systems, including the Lrg5+ stem cells in intestine [
      • Barker N.
      • et al.
      Crypt stem cells as the cells-of-origin of intestinal cancer.
      ] and epithelial progenitor cells in the skin [
      • Clayton E.
      • et al.
      A single type of progenitor cell maintains normal epidermis.
      ], with strikingly similar outcomes. However, fetal SMPCs have limited self-renewal potential and poor survival upon transplantation in vivo and lack a strong ability to form adult myotubes in vitro [
      • Hicks M.R.
      • et al.
      ERBB3 and NGFR mark a distinct skeletal muscle progenitor cell in human development and hPSCs.
      ]. It remains unknown whether these self-renewal defects are due to the fact that most transplantations are into matured adult microenvironments, such as during transplants of fetal SMPCs into adult muscle tissue, as it has not been tested in utero, where the developmental stage would more closely match the fetal niche. In other tissue systems, on the one hand, developmental timing has been shown to be important for cell competition following transplantation in which immature cells lose stemness when transplanted into more mature skin niches [
      • Ellis S.J.
      • et al.
      Distinct modes of cell competition shape mammalian tissue morphogenesis.
      ] or immature cells improve engraftment when transplanted into developing brain niches [
      • Hasselmann J.
      • et al.
      Development of a chimeric model to study and manipulate human microglia in vivo.
      ]. On the other hand, fetal SMPCs can be enriched at far greater numbers per gram of tissue than in the adult for therapeutic use but have limited true repopulation potential needed for use in cell-based therapies.

      Modeling emerging niche formation in vitro

      Directed differentiation of hPSCs to skeletal muscle is among the few robust in vitro systems able to increase PAX7 expression by 1000-fold [
      • Darabi R.
      • et al.
      Functional skeletal muscle regeneration from differentiating embryonic stem cells.
      ,
      • Chal J.
      • et al.
      Differentiation of pluripotent stem cells to muscle fiber to model Duchenne muscular dystrophy.
      ,
      • Choi I.Y.
      • et al.
      Concordant but varied phenotypes among Duchenne muscular dystrophy patient-specific myoblasts derived using a human iPSC-based model.
      ]. PAX7 cells not only are generated from hPSCs but also can be maintained in directed differentiation cultures for weeks to months [
      • Zhao M.
      • et al.
      Induced fetal human muscle stem cells with high therapeutic potential in a mouse muscular dystrophy model.
      ]. Directed differentiation produces an in vitro niche that is not equivalent to the typical well-studied adult niche. Across many lineages, differentiation of hPSCs results in phenotypes more closely aligned with embryonic to fetal progenitor cells [
      • Xi H.
      • et al.
      A human skeletal muscle atlas identifies the trajectories of stem and progenitor cells across development and from human pluripotent stem cells.
      ], and therefore, the niches that support hPSC muscle are more likely to be similar to an early developmental state. Just as with fetal development, an expected key component of emerging niches is the myofibers that are present in all directed differentiation strategies, and it is thought that secondary myogenesis in a dish can enhance maturation of Pax7 cells [
      • Al Tanoury Z.
      • et al.
      Differentiation of the human PAX7-positive myogenic precursors/satellite cell lineage.
      ]. During directed differentiation, many nonmyogenic lineages concurrently arise that may serve supportive functions through secretion of growth factors, ECM, cell–cell contact, or mechanical cues to create an in vitro niche for PAX7 SMPC generation. Many supportive cells found in emerging fetal niches (Table 1) are also found during directed differentiation, including neural progenitor cells, neurons, and mesenchymal cells, and, depending on the protocol, can also contain epithelial cells, skeletal cells, and chondrocytes. Depending on the timing and directed differentiation strategy, the supportive cells that emerge may differ [
      • Xi H.
      • et al.
      A human skeletal muscle atlas identifies the trajectories of stem and progenitor cells across development and from human pluripotent stem cells.
      ]. The role of these emerging populations has yet to be tested, but these populations have the potential to inform how to better generate or support PAX7 cells during human development.
      A cutting-edge area of emerging in vitro niches may include engineering 3D human skeletal muscle systems to provide a more long-term environment for support of PAX7 cells. In vitro myobundles have been developed that resemble the fetal myobundle niche and that exhibit calcium transients and nearby PAX7 SMPCs [
      • Rao L.
      • et al.
      Engineering human pluripotent stem cells into a functional skeletal muscle tissue.
      ]. Over a 4-week culture period, 3D induced skeletal muscle bundles undergo progressive myotube hypertrophy and functional enhancement and attain more advanced levels of myogenic differentiation than do age-matched 2D monolayers. In another format, induced myogenic progenitors (iMPCs) can undergo direct reprogramming and conversion to the myogenic program to generate spontaneously contractile myotubes with abutting Pax7+ cells near most fibers, suggesting the formation of in vitro emerging niches in an iMPC system [
      • Bar-Nur O.
      • et al.
      Direct reprogramming of mouse fibroblasts into functional skeletal muscle progenitors.
      ].
      Despite advances in generating PAX7 cells in 2D and 3D systems, there are currently still no protocols that can fully support or mature the equivalent of an adult muscle SC from hPSCs in vitro. Avenues to induce maturation could include addition of vascular cells, including endothelial cells, pericytes, or integration with motor neurons, to fully support generation of more mature adult SC-like cells in vitro. Recent work has shown that both muscle and neuronal cells can be generated in a new organoid system called the ‘neuromuscular organoid’ [
      • Faustino Martins J.M.
      • et al.
      Self-organizing 3D human trunk neuromuscular organoids.
      ], but whether this organoid model better supports developing or more mature adult PAX7 cells is not known. Vascular support would also improve survival of larger constructs in vitro and in vivo, which require vascularization to prevent hypoxia-induced cell death. Towards this end, it has been shown that generation of 3D muscle models alone, with injury [
      • Davoudi S.
      • et al.
      MEndR: an in vitro functional assay to predict in vivo muscle stem cell-mediated repair.
      ] or containing multiple supportive cells in addition to skeletal muscle, including vascular endothelial cells, pericytes, and motor neurons, can be generated, but the potential of PAX7 cells grown in 3D to engraft into the SC niche in vivo better than 2D conditions is still underway [
      • Maffioletti S.M.
      • et al.
      Three-dimensional human iPSC-derived artificial skeletal muscles model muscular dystrophies and enable multilineage tissue engineering.
      ].
      In addition, the in vivo environment may provide a better system for generating more mature and potentially quiescent adult SCs [
      • Incitti T.
      • et al.
      Pluripotent stem cell-derived myogenic progenitors remodel their molecular signature upon in vivo engraftment.
      ,
      • Sun C.
      • et al.
      Human pluripotent stem cell-derived myogenic progenitors undergo maturation to quiescent satellite cells upon engraftment.
      ]. However, even in these conditions, the maturation does not occur without serial transplantation in vivo and/or after injury. Recapitulating the in vivo niche in a dish will be needed to overcome these hurdles and generate an SC equivalent without the need to mature these cells in animal models.

      Generating new niches for therapeutics

      Regulating the stem cell niche set point

      Can we use the information gained from emerging niches to improve niche formation for use in regenerative medicine applications? Within any given organ, the niche tightly regulates the number of stem cells within it, termed the ‘niche set point’. The niche set point varies widely across organs; for example, the intestinal crypt, dental pulp, skin, and hair follicle bulge contain densely packed stem cells, whereas the liver and skeletal muscle niche contain more sparse stem cells [
      • Manesia J.K.
      • et al.
      Highly proliferative primitive fetal liver hematopoietic stem cells are fueled by oxidative metabolic pathways.
      ]. Understanding the cues that regulate the stem cell niche set points could be harnessed to potentially increase stem cell numbers in the niche and the robustness of the regenerative response [
      • Lane S.W.
      • et al.
      Modulating the stem cell niche for tissue regeneration.
      ].
      Emerging niches can be generated from hPSC SMPCs that recapitulate the early stages seen in muscle regeneration in vivo (M.R. Hicks et al., unpublished). During regeneration in the adult, new myofibers are formed, and PAX7 cells associate with regenerating myofibers [
      • Cutler A.A.
      • et al.
      The regenerating skeletal muscle niche guides muscle stem cell self-renewal.
      ]. Both in development and in regeneration, there are more SMPCs per unit of myofiber than at homeostasis, but whether we can regulate stem cell densities or set points is less well understood. This work suggests that a better understanding of the interaction of the SMPCs with the niche, perhaps in the context of emerging niche formation, similar to what is seen in regeneration, will provide clues as to how SMPCs can be remodeled to generate more functional SCs.
      It is interesting that as niches in development support more progenitor cells than the adult, it could be possible to rejuvenate the aging or diseased niches by recapitulating the niche set points, such as those that are created in development. Recently, overexpression of the Yamanaka factors (Oct3/4, Sox2, Klf4, and c-Myc) in myofibers caused changes to the myofibers, which included upregulation of cytoskeletal reorganization pathways and induced the activation of SCs, which could be similar to the SMPC state and in turn accelerated muscle regeneration in young mice [
      • Wang C.
      • et al.
      In vivo partial reprogramming of myofibers promotes muscle regeneration by remodeling the stem cell niche.
      ]. Regulation of the niche has also been accomplished using receptor–ligand combinations, such as using myofiber-derived Wnt4, which was shown to regulate the stem cell niche set point [
      • Eliazer S.
      • et al.
      Wnt4 from the niche controls the mechano-properties and quiescent state of muscle stem cells.
      ], and knockout of signaling pathways such as with Stat3 in the SCs that makes them nonresponsive to myofiber-induced signals such as with OSM [
      • Price F.D.
      • et al.
      Inhibition of JAK-STAT signaling stimulates adult satellite cell function.
      ]. Manipulating these or similar pathways in the emerging niches could help shift SMPCs toward an adult SC-like state.

      Modulating niche ECM/signaling

      It has been shown that injecting niche factors that target the receptors and ECM can modulate regeneration. For example, monoclonal antibody augmentation of β1-integrin activity can restore Fgf2 sensitivity and improve regeneration after experimentally induced muscle injury [
      • Rozo M.
      • et al.
      Targeting β1-integrin signaling enhances regeneration in aged and dystrophic muscle in mice.
      ]. To improve niche formation, it has been shown that treatment with fetal laminin-111 enhances symmetric cell division and improves regeneration in the adult, and this may harness aspects of a fetal-like regenerative state [
      • Rayagiri S.S.
      • et al.
      Basal lamina remodeling at the skeletal muscle stem cell niche mediates stem cell self-renewal.
      ]. A powerful tool to enhance regeneration may be to develop artificial niches to support SCs in vitro [
      • Quarta M.
      • et al.
      An artificial niche preserves the quiescence of muscle stem cells and enhances their therapeutic efficacy.
      ]. Others have also targeted the supportive cells in the microenvironment to regulate the regeneration through Notch signaling [
      • Verma M.
      • et al.
      Muscle satellite cell cross-talk with a vascular niche maintains quiescence via VEGF and Notch signaling.
      ], and depletion of niche cells reduces regeneration [
      • Wosczyna M.N.
      • et al.
      Mesenchymal stromal cells are required for regeneration and homeostatic maintenance of skeletal muscle.
      ].

      Aging and diseased niches

      It is important to note that the niche is not static but changes over the lifespan to regulate stem cell function in aging and disease contexts [
      • Voog J.
      • Jones D.L.
      Stem cells and the niche: a dynamic duo.
      ]. For example, in the aging intestinal niche, loss of barrier function in the epithelium alters stem cell fate [
      • Resnik-Docampo M.
      • et al.
      Tricellular junctions regulate intestinal stem cell behaviour to maintain homeostasis.
      ], and shifts in the number of Paneth cells in the niche reduce regenerative potential. In neurogenic niches, high vascular density and disruption of vascular remodeling in early development may play a long-term role in regulating neural organization, and vascular cell loss in the brain may be a contributor to neurodevelopmental disorders such as autism, schizophrenia, and epilepsy [
      • Shen Q.
      • et al.
      Adult SVZ stem cells lie in a vascular niche: a quantitative analysis of niche cell-cell interactions.
      ].
      Some of the worst muscle diseases occur from genetic defects in key components of the SC niche. Mutations in laminin-2 or collagen-6 genes result in congenital myopathies and Emery-Dreifuss disease, respectively, and lead to loss of Pax7 cells and muscle wasting [
      • Barraza-Flores P.
      • et al.
      Laminin and integrin in LAMA2-related congenital muscular dystrophy: from disease to therapeutics.
      ]. In one of the most devastating muscle-wasting diseases, Duchenne muscular dystrophy (DMD), SCs deficient in dystrophin lose polarity and are unable to appropriately form a niche, leading to a dysfunctional progenitor state, failed regeneration, and/or disease exacerbation [
      • Chang N.C.
      • et al.
      The dystrophin glycoprotein complex regulates the epigenetic activation of muscle stem cell commitment.
      ]. Recent work has shown that SCs survey their niche via cell protrusions [
      • Kann A.P.
      • et al.
      An injury-responsive Rac-to-Rho GTPase switch drives activation of muscle stem cells through rapid cytoskeletal remodeling.
      ], which, when impaired, such as in Piezo1 knockout or DMD, primes SCs to activate from quiescence [
      • Ma N.
      • et al.
      Piezo1 regulates the regenerative capacity of skeletal muscles via orchestration of stem cell morphological states.
      ].
      A key unresolved question is whether defects in emerging niche formation lead to incomplete maturation of the stem cell or a propensity for birth defects or developmental delays. Convincing evidence has demonstrated that some pediatric leukemias can originate before birth and that these cancers retain fetal niche properties postnatally [
      • Cazzola A.
      • et al.
      Prenatal origin of pediatric leukemia: lessons from hematopoietic development.
      ,
      • Rowe R.G.
      • et al.
      The developmental stage of the hematopoietic niche regulates lineage in MLL-rearranged leukemia.
      ]. Understanding the ontology of fetal hematopoiesis is of particular interest in understanding the pathogenesis of childhood blood disorders [
      • Wiemels J.L.
      • et al.
      Prenatal origin of acute lymphoblastic leukaemia in children.
      ]. Similarly, understanding how fetal skeletal muscle growth adapts to nutrient availability is important for determining deficits in muscle growth in adulthood. Because skeletal myofiber number is set at the time of birth, low birth weight infants may have lower muscle mass in adulthood, resulting in increased risk for metabolic syndrome and type 2 diabetes. Thus, suppressed development of muscle by inefficient niche formation or control could be a major contributor to increased risk of sarcopenia, obesity, or diabetes later in life [
      • Brown L.D.
      Endocrine regulation of fetal skeletal muscle growth: impact on future metabolic health.
      ].

      Concluding remarks

      Stem cell niches range in biological diversity across development to adulthood. The niches not only promote regeneration but also regulate the maturation and functional potential of the progenitors or stem cells they support. Niches should be considered as a therapeutic target to readily influence both intrinsic and extrinsic activity of progenitors and stem cells in development and disease. hPSCs offer a powerful system to generate robust regenerative cells, and this could have implications for use across many different cell-based therapeutic applications, especially if they can be directed to generate fully functional adult SCs. Evaluation of the differences in emerging compared with adult niches using new tools, including spatial sequencing, multiomics, and niche-specific computational platforms, will accelerate our understanding of how progenitor and stem cells are controlled differently in each niche state. Harnessing the power of emerging niches could shed light on new approaches to enhance regeneration and support human health (see Outstanding questions).
      What dictates progenitor differentiation versus niche formation?
      How does adherence to the emerging niche make the transition to adult SC niches over time?
      How do SMPCs transition into a quiescent SC?
      How many transitional states are there between fetal progenitor and adult stem cells?
      What regulates stem cell set point and number of niches across tissues?
      What are the roles of supportive cells in the emerging progenitor niche compared with the adult niche?
      What are similarities and differences between development and regeneration?
      Can new niches be rejuvenated in settings of aging or disease?
      Would the formation of new niches improve the rate or magnitude of regeneration?
      Is the myofiber plasma membrane specialized at the myofiber SC contact point, and how does this regulate SC set points?
      Can maturation of hPSC SMPCs be promoted by modulating the niche?
      What are the cues that are driving maturation in vivo?
      Are the processes that regulate the formation of the first niches from hPSCs the same as in vivo emerging niches?

      Acknowledgments

      A.D.P. is supported by NIH /NIAMS grant 2R01AR064327 and California Institute for Regenerative Medicine (CIRM) grant DISC2-10695 for aspects of this work, Ablon and Research Funds from BSCRC, and Ayoub Innovation Award support from UCLA . Support for M.H. comes from Muscular Dystrophy Association Developmental Award 629098 and the Institute for Clinical and Translational Science KL2 Program NIH/NCATS grant 5KL2TR001416 .

      Declaration of interests

      Dr. Pyle is co-founder and scientific advisory board member of MyoGene Bio.

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