key: cord-0846329-1p4a1i5q
authors: Ushakumary, Mereena George; Riccetti, Matthew; Perl, Anne‐Karina T.
title: Resident interstitial lung fibroblasts and their role in alveolar stem cell niche development, homeostasis, injury, and regeneration
date: 2021-02-24
journal: Stem Cells Transl Med
DOI: 10.1002/sctm.20-0526
sha: a9d32777985a96b93c7639fd38696a586c561216
doc_id: 846329
cord_uid: 1p4a1i5q

Developing, regenerating, and repairing a lung all require interstitial resident fibroblasts (iReFs) to direct the behavior of the epithelial stem cell niche. During lung development, distal lung fibroblasts, in the form of matrix‐, myo‐, and lipofibroblasts, form the extra cellular matrix (ECM), create tensile strength, and support distal epithelial differentiation, respectively. During de novo septation in a murine pneumonectomy lung regeneration model, developmental processes are reactivated within the iReFs, indicating progenitor function well into adulthood. In contrast to the regenerative activation of fibroblasts upon acute injury, chronic injury results in fibrotic activation. In murine lung fibrosis models, fibroblasts can pathologically differentiate into lineages beyond their normal commitment during homeostasis. In lung injury, recently defined alveolar niche cells support the expansion of alveolar epithelial progenitors to regenerate the epithelium. In human fibrotic lung diseases like bronchopulmonary dysplasia (BPD), idiopathic pulmonary fibrosis (IPF), and chronic obstructive pulmonary disease (COPD), dynamic changes in matrix‐, myo‐, lipofibroblasts, and alveolar niche cells suggest differential requirements for injury pathogenesis and repair. In this review, we summarize the role of alveolar fibroblasts and their activation stage in alveolar septation and regeneration and incorporate them into the context of human lung disease, discussing fibroblast activation stages and how they contribute to BPD, IPF, and COPD.

in the alveolar niche generate secondary septa, subsequently refining their architecture to reflect their function. Within the mesenchyme, interstitial resident fibroblasts play diverse and temporally critical roles in both alveolarization and alveolar regeneration. In the mouse, these alveolar fibroblasts are a mixed population of platelet derived growth factor receptor alpha (PDGFRa)-expressing fibroblasts. During alveolarization and alveolar regeneration, PDGFRa + myofibroblasts generate the mechanical force to extend the septal tip, and PDGFRa + matrix fibroblasts create ECM components to stabilize the newly formed septa, whereas PDGFRa + lipofibroblasts support AT2 cell function during homeostasis. [2] [3] [4] [5] [6] Moreover, recently defined alveolar niche cells, marked by PDGFRa and Axin2/Wnt2/Lgr5 coexpression, support alveolar epithelial regeneration after injury. 7 All four of these cell populations arrive at precisely the right time to provide both the scaffold and the paracrine signals the epithelium needs to proliferate and differentiate. The advent of single-cell RNA sequencing (scRNAseq) and the refinement of inducible mouse lineage-tracing systems have yielded a plethora of data on the interstitial lung fibroblast during alveolarization, [6] [7] [8] [9] [10] [11] [12] but individually analyzing these data can be overwhelming. In this review, we summarize the role of alveolar fibroblasts in alveolar septation and regeneration and incorporate them into context of how they are modified in and contribute to human lung diseases like BPD, IPF, and COPD.

Since the mid-1990s, the importance of the alveolar mesenchyme in directing alveolar epithelial proliferation and differentiation has become the focus of several studies. 13, 14 Alveolar fibroblasts:

(a) provide and modulate an ECM scaffold for epithelial cells to expand upon, (b) provide tensile forces to extend and thin the septal walls during secondary septation, and (c) provide paracrine cues to the surrounding epithelium and endothelium to initiate proliferation and differentiation. During development, alveolar fibroblasts can be defined as four functional populations: myofibroblasts, lipofibroblasts, matrixfibroblasts, and alveolar niche cells. 15 These four populations cover all functions of the alveolar fibroblast but have been described as several fibroblast lineages that partially overlap. Based on individual localization and PDGFRα expression they have been called interstitial resident fibroblasts, "iReF," 2,15 or alveolar niche cells. 7 We will discuss interstitial fibroblasts in the formation of the alveolus during development, their role during reseptation after partial pneumonectomy (PNX), and their role in disease formation and progression.

Interstitial fibroblast function during alveolarization Pulmonary interstitial fibroblasts are critical for the formation and extension of alveolar septa postnatally but already prepare for septation prenatally. The alveolus is architecturally conserved between the human and murine peripheral lung. 16, 17 Mice are born in the saccular phase, and alveolarization is observed postnatally, whereas human alveolarization starts at around 36 weeks of gestation. Babies born before 36 weeks of gestation are therefore born in the saccular stage of lung development and are susceptible to barotrauma and hyperoxia-induced damage, contributing to the chronic lung injury seen in BPD. [17] [18] [19] As alveolarization occurs postnatally in mice, and interventions like hyperoxia and pharmacological treatments are amenable in neonatal mice, the murine system is highly valuable to study alveolarization and BPD. 20 Here, we summarize the temporal role of myo-, matrix, lipo-, and alveolar niche cell fibroblasts in the process of alveolarization.

A temporal comparison of human and murine alveolarization and the functional roles of interstitial fibroblasts are illustrated in Figure 1 . PN3-PN14, human: 1-18 months after birth). 21, 28 These myofibroblasts also produce a framework of elastin and tenascin, supporting the newly forming secondary crest. As the myofibroblast contracts, it is assumed to pull the ECM that the matrixfibroblast beneath is actively making. 2,10,29-37 As secondary crests form and elongate, endothelial cells 22, 26, 27, 31, [37] [38] [39] [40] [41] [42] [43] [44] [45] [46] [47] [48] During and after septation, lipofibroblasts align themselves with AT2 cells and support their proliferation and differentiation to AT1 cells. 34, [49] [50] [51] [52] [53] [54] [55] As the septa mature, matrix and myofibroblasts secrete metalloproteinases and other ECM-remodeling proteins to thin the septal tip ECM. 2, 29, 35, 40, [56] [57] [58] [59] [60] [61] [62] [63] The secondary-crest myofibroblast continues producing elastin, eventually undergoing apoptosis during adulthood. 5, 31, 32, 34, [64] [65] [66] Lipofibroblasts continue to support AT2 cell surfactant production. 53, 55, 67, 68 At the end of alveolarization, adult stem cell niches become defined, consisting of the lipofibroblast-like alveolar niche cell (also called mesenchymal alveolar niche cell, MANC) and the alveolar epithelial progenitor (AEP). 7, [69] [70] [71] [72] The process of alveolarization, depicted in Figure 1 , requires temporal and coordinated activity of functionally distinct fibroblast stages. In order for fibroblasts to acquire specific functions, inductive and reciprocal autocrine and epithelial or endothelial-derived paracrine signals are required. Selective signature genes of these cellular players are listed next to the cellular key in Figure 1 [73] [74] [75] [76] (LGEA: https://research.cchmc. org/pbge/lunggens/mainportal.html). 77 Signaling pathways specify fibroblast subpopulations and control fibroblast function myofibroblasts as a lack of SHH signaling blocks myofibroblast differentiation. 3, 32, [85] [86] [87] The BMP/SMAD signaling pathway is reported to regulate alveolar stem cell proliferation and differentiation. PDGFRa + myofibroblasts produce BMP4, which acts antagonistically to WNT and regulates AT2 cell renewal, differentiation, and regeneration. 69 Alveolar niche cells produce WNT ligands, which act mainly through canonical WNT signaling to replenish the AXIN2+ epithelial progenitor pool during development and repair. 7, 70, 71, 88 Thus, all these fibroblast stages are integrated to form a fully functional alveolar niche. To aid in visualization, many of these signaling ligands that are specific to certain fibroblast subtypes during development are pictured in the legend of Figure 1 . Further information about pulmonary fibroblast lineages during development can be found in a recent review that details the pathways and mice used for lineage-tracing studies in the mesenchyme. 15 Besides these common and developmentally conserved pathways, hormones and steroids are emerging as significant modulators of fibroblast differentiation in the lung. 89 

Although adult compensatory lung growth is restricted in humans, 90 unilateral left lobe PNX in mice initiates realveolarization in the remaining right lobes. PNX is an excellent model system to study molecular and cellular mechanisms of alveolar regeneration but does not recapitulate injury response. During realveolarization, myofibroblasts are critical to extend new septa (reseptation), and matrixfibroblasts are required for the production of new ECM to stabilize the septa. 29 The different fibroblast stages in reseptation after PNX are visualized in Figure 2A , shown to induce lipofibroblast differentiation. 93 In the context of injury response, rosiglitazone treatment significantly reduced transforming growth factor beta (TGFβ)-mediated myofibroblast differentiation. During regeneration following PNX, rosiglitazone treatment inhibited reseptation as myofibroblast activation in PDGFRa + fibroblasts was blocked. 29 These data suggest PPARγ signaling as both an inhibitor of myofibroblast differentiation and an activator of lipofibroblast differentiation and support the theory that lipo-to myofibroblast differentiation is necessary to drive new septa formation. 94 These regeneration studies revealed molecular drivers and cell type-specific roles of fibroblasts during reseptation. In the future, the use of transgenic mice with gene activation and inactivation before PNX surgery or during regeneration has great potential for discerning the molecular regulation of regeneration.

Age-specific decline in alveolar regeneration has been investigated in murine models after PNX. Decreased fibroblast clonality and increased myofibroblast differentiation impair reseptation in aged mice compared with young mice. [95] [96] [97] In addition, perinatal hyperoxia exposure has recently been linked to the induction of senescence in the mesenchyme and is demonstrated to be a cause of BPD. 98 Priming aged mice with epigenetic modifiers to study gene silencing in the context of failed lung regeneration has translational application for initiating regeneration in human lungs. Although the murine PNX model gives insight into the role of fibroblasts during reseptation, a plethora of murine lung fibrosis models has been used to study the contribution of fibroblasts in chronic lung disease.

Bleomycin injury has been extensively used to study acute lung fibrosis and the contribution of various cell types to the fibrotic response.

Mechanical and paracrine cues from the site of injury regulate 

IPF is characterized by extensive fibrosis, causing progressive respiratory decline and mortality, usually within 5 years of diagnosis. [107] [108] [109] Although the pathogenesis of IPF remains unclear, chronic alveolar epithelial cell injury and chronic fibrotic activation of fibroblasts are linked to the disorder. 110 Treatment regimens using pirfenidone and nintedanib showed effectiveness in reducing morbidity but not mortality. 111, 112 Considerable effort has been taken to study the role and origin of fibroblasts as they are promising targets of antifibrotic therapy.

At the tissue level, IPF is defined by a fibroblastic focus with an immature hyaluronic acid-rich matrix underneath the epithelial layer, loss of alveolar type 1 cell differentiation, and increased αSMA+ myofibroblasts. 113 The presence of epithelial basal-like cells that coexpress epithelial and mesenchymal markers has been reported in IPF lungs by scRNA-seq. 6 These indeterminate alveolar type 2 cells were found to be located at the edge of myofibroblast foci in the IPF lung. 8 Despite its limitations, bleomycin injury in mice has been used to model and study IPF. In both human IPF samples and murine models of pulmonary fibrosis, the myofibroblast population expands considerably. [114] [115] [116] Myofibroblasts arise from both resident myofibroblasts and resident lipofibroblasts, 117 suggesting aberrant fibrotic activation in a variety of fibroblast populations. In the bleomycin injury model, interstitial lung fibroblasts, pericytes, and mesothelial cells are known to differentiate into myofibroblasts. Partial epithelial-mesenchymal transition has also been reported using multiple reported systems and injury models. [118] [119] [120] Lipofibroblasts, whose existence was once questioned in the adult human lung, have recently been identified as a stable cell population during homeostasis using scRNA-seq. 47 Studies of lipofibroblast function in the murine lung indicate a role in fibrosis. As previously mentioned, PDGFRα-expressing lipofibroblasts differentiate into myofibroblasts upon injury and transdifferentiate back to lipofibroblasts during fibrosis resolution in the mouse lung. 78, 100, 117 In IPF, lipofibroblasts are prominent 121 ; however, the relative mRNA expression of canonical lipofibroblast markers PLIN2, PPARγ, and TCF21 is reduced. 117 Another study using freshly isolated PDGFRa-expressing fibroblasts from IPF lungs showed that PDGFRa + lipofibroblasts shift to a PDGFRa + myofibroblast stage/activation. Moreover, PDGFRa + matrixfibroblasts are significantly reduced in IPF lungs. 122 

Hyperoxic and hyperbaric conditions due to supplemental oxygen in association with premature birth cause disruption of alveologenesis, resulting in permanent alveolar simplification (BPD). 124 Because of medical advances like antenatal steroid treatment and neonatal surfactant therapy, the fibrotic pathophysiology of "Old" BPD as described by Northway is rarely seen. 125 The "New" BPD, constituting alveolar simplification via arrest of lung development, remains a prominent comorbidity of premature birth today. 126, 127 The injury is further characterized by damage to the lung epithelial cells that normally facilitate gas exchange and disruption in vascular development, particularly alveolar capillaries. 128 Unraveling the molecular mechanisms of fibroblast response to hyperoxia is essential to develop new strategies for the prevention of BPD. As previously mentioned, PDGFRα signaling is necessary for the normal functioning myofibroblasts that drive alveolar septation during distal lung development. 13 Figure 2B .

BPD has recently been identified as a risk factor for COPD and severity of Coronavirus disease 2019 in both murine models and epidemiological studies, highlighting the importance of understanding the long-term consequences of BPD. [135] [136] [137] [138] Limitations and alternative models for BPD

In vitro studies are a reductionist approach that is inherently limited because of a lack of cellular microenvironmental context. On the other hand, the in vivo murine hyperoxia model is limited as mice are naturally born in the saccular phase. 139 To interrupt lung development during lung sacculation and simultaneously recapitulate BPD, rabbit kits can be delivered via c-section and subjected to mechanical ventilation. 140, 141 Modeling of BPD in sheep and nonhuman primates is expensive but provides excellent alternatives to better understand human lung development and BPD. [142] [143] [144] [145] [146] The recent development of organoid and precision-cut lung slice (PCLS) models recapitulate certain aspects of hyperoxia exposure during alveolarization. Exposure of three-dimensional organotypic coculture to hyperoxia mimics aspects of BPD pathogenesis, including activation of ACTA2 and COL1A1 expression in fibroblasts. 147 Ex vivo PCLS exposed to hyperoxia maintain some features of pulmonary architecture and facilitate live imaging studies to assess cellular migration, proliferation, and differentiation. 147 To advance the field of BPD,

we will have to integrate findings from old and newly developing BPD model systems, with transcriptomic and proteomic analysis.

Irreversible airway obstruction 148 with emphysematous changes, such as loss of elastic fibers in the alveolar walls and subsequent destruction of the alveoli, define the pathology of COPD. 149 Reduced fibroblast proliferation and altered repair mechanisms contribute to the emphysematous lung. 150 A role for TGFβ1 has been reported in COPD patients compared with healthy control patients 151 and showed that COPD fibroblasts are less responsive to TGFβ1 in terms of proliferation and elastin production compared with normal fibroblasts. 152 Fibroblasts from moderate to severe COPD subjects show a secretory phenotype with upregulation of inflammatory molecules and increased soluble elastin. The formation of soluble elastin was inhibited by versican, an inflammatory matrix proteoglycan, which is predominately expressed in myofibroblasts. 153 Furthermore, studies on COPD fibroblasts also show less chemotactic activity and collagen contraction. 154 Although interstitial fibroblasts are important for septal tip formation and elastin deposition during development and repair, their role in COPD has not been studied. Investigating mechanisms and consequences to understand the association of functional fibroblast stages and ECM damage may pave the way for better outcomes.

The advent of scRNA-seq has greatly strengthened the understanding of fibroblast heterogeneity within the lung field but, at the same time, 

The authors declared no potential conflicts of interest.

A.K.P., M.G.U. and M.R. wrote the manuscript. M.R. created the figures.

Data sharing is not applicable to this article as no new data were created or analyzed in this study.

Mereena George Ushakumary https://orcid.org/0000-0002-0671-6611

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How to cite this article: Ushakumary MG, Riccetti M, Perl A-KT. Resident interstitial lung fibroblasts and their role in alveolar stem cell niche development, homeostasis, injury, and regeneration