Epithelial Interactions and Local Engraftment of Lung-Resident Mesenchymal Stem Cells

Badri, Linda; Walker, Neff; Ohtsuka, Takashi; Wang, Zhuo; Delmar, Mario; Flint, Andrew; Peters‐Golden, Marc; Toews, Galen B.; Pinsky, David J.; Krebsbach, Paul H.; Lama, Vibha N.

doi:10.1165/rcmb.2010-0446oc

Cited by 62 publications

(65 citation statements)

References 39 publications

(8 reference statements)

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“…In clinical transplant allografts, Lama and colleagues (32) have demonstrated evidence of donor-derived lung-resident mesenchymal stem cells and that these cells establish interactions with both airway and alveolar epithelium and secrete growth factors necessary for proliferation and differentiation (4). IL-17A has recently been highlighted as a profibrotic cytokine in murine models of idiopathic pulmonary fibrosis (51) and has been reported to have profibrotic effects in renal epithelial cells (18) and human mesenchymal stem cells (25).…”

Section: L409 Il-17 Mediated Col(v) Overexpression and Emtmentioning

confidence: 99%

IL-17 induces type V collagen overexpression and EMT via TGF-β-dependent pathways in obliterative bronchiolitis

Vittal¹,

Fan²,

Greenspan³

et al. 2013

American Journal of Physiology-Lung Cellular and Molecular Phys

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erative bronchiolitis (OB), a fibrotic airway lesion, is the leading cause of death after lung transplantation. Type V collagen [col(V)] overexpression and IL-17-mediated anti-col(V) immunity are key contributors to OB pathogenesis. Here, we report a previously undefined role of IL-17 in inducing col(V) overexpression, leading to epithelial mesenchymal transition (EMT) and subsequent OB. We observed IL-17-mediated induction of col(V) ␣1 chains [␣1 (V)] in normal airway epithelial cells in vitro and detected ␣1 (V)-specific antibodies in bronchoalveolar lavage fluid of lung transplant patients. Overexpression of IL-17 and col(V) was detected in OB lesions in patient lung biopsies and in a murine OB model. IL-17 is shown to induce EMT, TGF-␤ mRNA expression, and SMAD3 activation, whereas downregulating SMAD7 expression in vitro. Pharmacological inhibition of TGF-␤RI tyrosine kinase, p38 MAPK, or focal adhesion kinase prevented col(V) overexpression and EMT. In murine orthotopic lung transplants, neutralizing IL-17 significantly decreased TGF-␤ mRNA and protein expression and prevented epithelial repair/ OB. Our findings highlight a feed-forward loop between IL-17 and TGF-␤, leading to induction of col(V) and associated epithelial repair, thus providing one possible link between autoimmunity and OB after lung transplantation. autoimmunity; p38 MAPK; focal adhesion kinase; small-airway epithelial cells; RLE-6TN; mouse transplant model; epithelial-mesenchymal transition OBLITERATIVE BRONCHIOLITIS (OB) is characterized by extensive peribronchiolar fibrosis with plugs of granulation tissues (fibroblasts and collagen) that occlude small airways. OB is the key reason that the 5-yr survival of lung transplant recipients is only 50%, the worst of all major solid organ transplants (42,48).Aberrant epithelial repair is a key event in the transplanted lung (1, 9) in which bronchioles lose resident epithelial cells and become occluded by granulation tissue. Abnormal epithelial repair eventually causes an epithelial-to-mesenchymal transition (EMT), a functional and phenotypic change of epithelial cells into spindle-shaped, migratory (43) and matrix-component-secreting mesenchymal cells (10, 41), and a process associated with lung fibrosis (15,27). However, the direct connection between EMT and the in vivo phenomena of fibrosis and fibro-obliterative disease remains controversial.We and others previously reported that OB is associated with dysregulation of two types of collagen: 1) marked increase in type V collagen [col(V)], a quantitatively minor lung collagen (8,14,40), and 2) a decrease in the major lung collagen type I [col(I)] (2, 53). We have shown that prospective monitoring of patients with human lung transplant revealed a critical role of col(V)-specific cellular immunity in OB pathogenesis (14,40). Although overexpression of col(V), an otherwise quantitatively minor collagen, is involved in OB pathology, mechanisms leading to col(V) overexpression are unknown. Thus a mechanistic understanding of the triggers of col(V)...

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Section: L409 Il-17 Mediated Col(v) Overexpression and Emtmentioning

confidence: 99%

IL-17 induces type V collagen overexpression and EMT via TGF-β-dependent pathways in obliterative bronchiolitis

Vittal¹,

Fan²,

Greenspan³

et al. 2013

American Journal of Physiology-Lung Cellular and Molecular Phys

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“…Dr. Lama found that, in contrast to bone marrow-derived MSCs, lung resident MSCs (LR-MSCs) exhibit increased Foxf1, Hoxa5, and Hoxb5 transcription factors and are preferentially located near endothelial tissues adjacent to alveolar septae (61). Although the function of these cells in lung homeostasis and repair remains incompletely understood, Dr. Lama suggested that LR-MSCs may provide a supportive microenvironment for epithelial progenitor cells while also contributing to the pathogenesis of fibrotic lung disease (61,62). Finally, she provided evidence that patients at increased risk of developing bronchiolitis obliterans exhibited elevated LR-MSC abundance in their bronchiolar lavage fluid.…”

Section: American Thoracic Society Documentsmentioning

confidence: 99%

An Official American Thoracic Society Workshop Report: Stem Cells and Cell Therapies in Lung Biology and Diseases

Weiss¹,

Chambers²,

Giangreco³

et al. 2015

Annals ATS

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The University of Vermont College of Medicine and the Vermont Lung Center, in collaboration with the NHLBI, Alpha-1 Foundation, American Thoracic Society, European Respiratory Society, International Society for Cell Therapy, and the Pulmonary Fibrosis Foundation, convened a workshop, "Stem Cells and Cell Therapies in Lung Biology and Lung Diseases," held July 29 to August 1, 2013 at the University of Vermont. The conference objectives were to review the current understanding of the role of stem and progenitor cells in lung repair after injury and to review the current status of cell therapy and ex vivo bioengineering approaches for lung diseases. These are all rapidly expanding areas of study that both provide further insight into and challenge traditional views of mechanisms of lung repair after injury and pathogenesis of several lung diseases. The goals of the conference were to summarize the current state of the field, discuss and debate current controversies, and identify future research directions and opportunities for both basic and translational research in cell-based therapies for lung diseases. This conference was a follow-up to four previous biennial conferences held at the University

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“…Mesenchymal stem cells (MSCs), originating from bone marrow, adipose tissue, umbilical cord blood and many other tissues, are multipotent stem cells that have proliferative and self-renewal potential and that can differentiate into multi-lineage cell types, including osteoblasts, chondrocytes, adipocytes, myocytes, cardiomyocytes, neurons and epithelial cells (Badri et al 2011;Deng et al 2005;Lee et al 2011a;Li et al 2006;Moreno et al 2010;Sterodimas et al 2011;Zanier et al 2011). In contrast to hematopoietic stem cells that express specific cell surface markers, MSCs express numerous surface antigens but none are exclusive, so the phenotypic identify of MSCs shares features of multiple cell lineages (Bobis et al 2006;Huss 2000).…”

Section: Introductionmentioning

confidence: 99%

Mechanisms of action of mesenchymal stem cells in cutaneous wound repair and regeneration

2012

Cell Tissue Res

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Mesenchymal stem cells (MSCs) are multipotent cells with the capacity for self-renewal and differentiation and have a broad tissue distribution. These characteristics make them candidate cells for wound healing and regeneration in a variety of disorders. Endogenous MSCs or exogenously delivered MSCs can traffic and migrate to injured tissue and participate in the healing of this tissue. The concentrated conditioned medium from MSCs can modulate wound repair without MSCs being present in the wound. The therapeutic effects of MSCs might be attributable to their ability to differentiate and transdifferentiate into tissue-specific cells, to fuse with the resident cells, to secrete a wide array of paracrine factors in order to stimulate the survival and functional recovery of the resident cells, or to regulate the local microenviroment or niche and immune response. These mechanisms are probably independent but not mutually exclusive. In many circumstances, a combination of these protective mechanisms might work together to affect cutaneous wound healing. This review gives a brief overview and discusses the mechanisms by which MSCs promote skin repair and regeneration, although the specific mechanisms in each type of cutaneous wound are still unclear and controversial. A comprehensive understanding of the mechanisms should allow us to find advanced and better treatment strategies for various skin diseases, even those that are currently incurable.

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Epithelial Interactions and Local Engraftment of Lung-Resident Mesenchymal Stem Cells

Cited by 62 publications

References 39 publications

IL-17 induces type V collagen overexpression and EMT via TGF-β-dependent pathways in obliterative bronchiolitis

IL-17 induces type V collagen overexpression and EMT via TGF-β-dependent pathways in obliterative bronchiolitis

An Official American Thoracic Society Workshop Report: Stem Cells and Cell Therapies in Lung Biology and Diseases

Mechanisms of action of mesenchymal stem cells in cutaneous wound repair and regeneration

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