Evidence for tissue-resident mesenchymal stem cells in human adult lung from studies of transplanted allografts

Lama, Vibha N.; Smith, Lisa M.; Badri, Linda; Flint, Andrew; Andrei, Adin Cristian; Murray, Susan; Wang, Zhuo; Liao, Hui; Toews, Galen B.; Krebsbach, Paul H.; Peters‐Golden, Marc; Pinsky, David J.; Martínez, Fernando J.; Thannickal, Victor J.

doi:10.1172/jci29713

Cited by 287 publications

(268 citation statements)

References 43 publications

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“…As a primary effector cell of fibrogenesis, mesenchymal cells play a key role in CLAD arising from OB or parenchymal fibrosis. While mesenchymal cells orchestrating fibrosis can potentially be derived from various sources, the mesenchymal population in the transplanted lung retains its donor origin and these graft-derived cells appear to be the predominant contributors to OB lesions (98,(128)(129)(130)(131). Investigation of fibrotic lesions in the HTT model have shown them to be derived from the recipients (132).…”

Section: Cladmentioning

confidence: 99%

Models of Lung Transplant Research: a consensus statement from the National Heart, Lung, and Blood Institute workshop

Lama¹,

Belperio²,

Christie³

et al. 2017

JCI Insight

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Section: Cladmentioning

confidence: 99%

Models of Lung Transplant Research: a consensus statement from the National Heart, Lung, and Blood Institute workshop

Lama¹,

Belperio²,

Christie³

et al. 2017

JCI Insight

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“…Alveolar mesenchymal cells were isolated and cultured from bronchoalveolar lavage of human subjects with IPF, as previously described (21). All studies were approved by the Institutional Review Boards at the University of Michigan and the University of Alabama at Birmingham.…”

Section: Cell Culturementioning

confidence: 99%

The matricellular protein CCN1 enhances TGF‐β1/SMAD3‐dependent profibrotic signaling in fibroblasts and contributes to fibrogenic responses to lung injury

Kurundkar

Rangarajan

et al. 2016

FASEB j.

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Matricellular proteins mediate pleiotropic effects during tissue injury and repair. CCN1 is a matricellular protein that has been implicated in angiogenesis, inflammation, and wound repair. In this study, we identified CCN1 as a gene that is differentially up-regulated in alveolar mesenchymal cells of human subjects with rapidly progressive idiopathic pulmonary fibrosis (IPF). Elevated levels of CCN1 mRNA were confirmed in lung tissues of IPF subjects undergoing lung transplantation, and CCN1 protein was predominantly localized to fibroblastic foci. CCN1 expression in ex vivo IPF lung fibroblasts correlated with gene expression of the extracellular matrix proteins, collagen (Col)1a1, Col1a2, and fibronectin as well as the myofibroblast marker, a-smooth muscle actin. RNA interference (RNAi)-mediated knockdown of CCN1 down-regulated the constitutive expression of these profibrotic genes in IPF fibroblasts. TGF-b1, a known mediator of tissue fibrogenesis, induces gene and protein expression of CCN1 via a mothers against decapentaplegic homolog 3 (SMAD3)-dependent mechanism. Importantly, endogenous CCN1 potentiates TGF-b1-induced SMAD3 activation and induction of profibrotic genes, supporting a positive feedback loop leading to myofibroblast activation. In vivo RNAi-mediated silencing of CCN1 attenuates fibrogenic responses to bleomycin-induced lung injury. These studies support previously unrecognized, cooperative interaction between the CCN1 matricellular protein and canonical TGF-b1/SMAD3 signaling that promotes lung

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“…15,16 Surface marker expression for cells used in the present study was determined using flow cytometry. LR-MSCs were negative for CD45 and positive for CD73, CD105, CD90, and CD44.…”

Section: Isolation Of Lung-derived Mscs and Other Cell Linesmentioning

confidence: 99%

“…15 These cells are of predominantly donor origin in studies of sex-mismatched lung allografts, suggesting they are a lung-resident (LR) population of connective tissue progenitors. 15 However, whether these LR-MSCs represent a tissue-specific cell, the potential remnant of embryonic lung mesenchyme remains unknown. Furthermore, whether these cells participate in fibrogenesis in a lung allograft remains to be determined.…”

mentioning

confidence: 99%

Resident Tissue-Specific Mesenchymal Progenitor Cells Contribute to Fibrogenesis in Human Lung Allografts

Walker

Badri

Wettlaufer

et al. 2011

The American Journal of Pathology

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105

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Fibrotic obliteration of the small airways leading to progressive airflow obstruction, termed bronchiolitis obliterans syndrome (BOS), is the major cause of poor outcomes after lung transplantation. We recently demonstrated that a donor-derived population of multipotent mesenchymal stem cells (MSCs) can be isolated from the bronchoalveolar lavage (BAL) fluid of human lung transplant recipients. Herein, we study the organ specificity of these cells and investigate the role of local mesenchymal progenitors in fibrogenesis after lung transplantation. We demonstrate that human lung allograft-derived MSCs uniquely express embryonic lung mesenchyme-associated transcription factors with a 35,000-fold higher expression of forkhead/winged helix transcription factor forkhead box ( Chronic allograft rejection develops in up to 60% of patients who undergo lung transplantation by 5 years and is the leading cause of poor long-term outcomes after lung transplantation.1 As with other solid organ transplants, chronic allograft rejection in the lung manifests as a fibrotic response to repeated immune and nonimmune insults, leading to narrowing and obliteration of the small airways, a lesion termed bronchiolitis obliterans (BO). 2Subepithelial and/or intraluminal infiltration by myofibroblasts, differentiated mesenchymal cells with augmented collagen secretory and contractile functions, 3 is noted in human biopsy specimens that demonstrate BO.4 BO presents clinically as an obstructive ventilatory defect termed BO syndrome (BOS).5 BOS is the major cause of graft failure and long-term mortality, with no effective treatment options. 6,7 Understanding the origin of effector myofibroblasts in fibrotic lesions of BO is critical for therapeutic targeting of mechanisms of cell recruitment/differentiation.One potential source of mesenchymal cells participating in this disorganized repair response is the mesenchymal progenitors residing in the graft. The embryonic lung mesenchyme is derived from splanchnic mesoderm during orSupported by grants (R01DK082481 to P.H.K.; RO1HL094311 to M.P.-G.; RO1HL094622

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Evidence for tissue-resident mesenchymal stem cells in human adult lung from studies of transplanted allografts

Cited by 287 publications

References 43 publications

Models of Lung Transplant Research: a consensus statement from the National Heart, Lung, and Blood Institute workshop

Models of Lung Transplant Research: a consensus statement from the National Heart, Lung, and Blood Institute workshop

The matricellular protein CCN1 enhances TGF‐β1/SMAD3‐dependent profibrotic signaling in fibroblasts and contributes to fibrogenic responses to lung injury

Resident Tissue-Specific Mesenchymal Progenitor Cells Contribute to Fibrogenesis in Human Lung Allografts

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