Hyaluronidase recruits mesenchymal-like cells to the lung and ameliorates fibrosis

Bitencourt, Claudia S.; Pereira, Priscilla At; Ramos, Simone G.; Sampaio, Suely Vilela; Arantes, Eliane Candiani; Aronoff, David M.; Faccioli, Lúcia Helena

doi:10.1186/1755-1536-4-3

Cited by 53 publications

(39 citation statements)

References 43 publications

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“…Cell culture data have suggested that the loss of the defining differentiation potential of MSCs occurs in a hierarchical manner, whereby the ability for adipogenic differentiation is commonly abolished first prior to the loss of the chondrogenic differentiation potential, finally giving rise to osteogenic precursor cells4243. The observed reduction in the differentiation potential of MSCs may bear therapeutic significance, as previous publications have reported regenerative effects of mobilized endogenous MSCs in bleomycin-induced pulmonary fibrosis4445. In these datasets, pulmonary damage was mostly induced by topical intratracheal instillation of bleomycin, thereby preserving MSCs of other tissues46.…”

Section: Discussionmentioning

confidence: 99%

Mesenchymal stem cells are sensitive to bleomycin treatment

Nicolay

Rühle

Perez

et al. 2016

Sci Rep

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Mesenchymal stem cells (MSCs) have been shown to attenuate pulmonary damage induced by bleomycin-based anticancer treatments, but the influence of bleomycin on the stem cells themselves remains largely unknown. Here, we demonstrate that human bone marrow-derived MSCs are relatively sensitive to bleomycin exposure compared to adult fibroblasts. MSCs revealed increased levels of apoptosis after bleomycin treatment, while cellular morphology, stem cell surface marker expression and the ability for adhesion and migration remained unchanged. Bleomycin treatment also resulted in a reduced adipogenic differentiation potential of these stem cells. MSCs were found to efficiently repair DNA double strand breaks induced by bleomycin, mostly through non-homologous end joining repair. Low mRNA and protein expression levels of the inactivating enzyme bleomycin hydrolase were detected in MSCs that may contribute to the observed bleomycin-sensitive phenotype of these cells. The sensitivity of MSCs against bleomycin needs to be taken into consideration for ongoing and future treatment protocols investigating these stem cells as a potential treatment option for bleomycin-induced pulmonary damage in the clinic.

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Section: Discussionmentioning

confidence: 99%

Mesenchymal stem cells are sensitive to bleomycin treatment

Nicolay

Rühle

Perez

et al. 2016

Sci Rep

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“…Chemokine (CC motif) ligand 2/monocyte chemotactic protein-1 (CCL2/MCP-1) is involved in inflammatory lung disorders and can recruit leukocytes, stimulate histamine or leukotriene release from mast cells or basophils, and induce the fibroblast production of TGF-b1 and procollagen, with enhanced Th2 polarization (67). Hyaluronidases (HYALs) comprise a group of enzymes that degrade hyaluronic acid (HA), and with the HYAL treatment, TGF-b1 production and collagen deposition are decreased in bleomycin-induced lung injury while fibrosis is potently blocked (68). In airway epithelial, Src homology 2 protein tyrosine phosphatase (SHP2), a modulator of TGFb1 production, appears to modulate the TGF-b1 activity and in turn regulate allergic airway remodeling after allergen provocation in mouse models (69).…”

Section: Other Pathwaysmentioning

confidence: 99%

Transforming growth factor‐beta 1 pathways in inflammatory airway diseases

Yang

Zhang

Feng

et al. 2014

Allergy

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Transforming growth factor-beta 1 (TGF-b1) has been reported being involved in the remodeling and immunosuppression processes of inflammatory airway diseases; understanding the regulation of TGF-b1 is therefore a key to unravel the pathomechanisms of these diseases. This review briefly summarizes the current knowledge on the influencing factors for driving TGF-b1 and its regulatory pathways in inflammatory airway diseases and discusses possible therapeutic approaches to TGF-b1 control. The factors include smoking and oxidative stress, prostaglandins (PGs), leukotrienes (LTs), bradykinin (BK), and microRNAs (miRs). Based on the summary, new innovative treatment strategies may be developed for inflammatory airway diseases with an impaired expression of TGF-b1.The transforming growth factor-beta (TGF-b) superfamily is critically involved in embryonic development, organogenesis, and tissue homeostasis. It acts as multifunctional regulators of cell growth and differentiation and consists of more than 40 members, mainly including TGF-bs, bone morphogenetic proteins (BMPs), growth and differentiation factors (GDFs), activins, and inhibins. Between these superfamily members, there is a complex network of regulatory mechanisms (1, 2).Possessing immunomodulatory and fibrogenic characteristics, TGF-b1 is a pleiotropic and multifunctional cytokine secreted from various types of cells, such as endothelial, epithelial and smooth muscle cells, as well as fibroblasts and most immune system cells.Transforming growth factor-beta 1 regulation is unique because it is targeted to the extracellular matrix as a biologically inactive complex, which consists of a mature 25-kDa polypeptide dimer (TGF-b), a latency-associated protein (LAP), and a latent TGF-b-binding protein (LTBP). Active TGF-b is released from the latent complex that was activated via cleavage by proteases and other molecules. The activated TGF-b then becomes a ligand for TGF-b type I and II receptors, leading to receptor Smad (R-Smad) phosphorylation, which subsequently binds to the common-partner Smad (co-Smad), and becoming Smad complexes. The Smad complexes translocate into the nucleus and combine with several transcription factors, thereby becoming a transcriptional active complex that activates target genes transcription. In Abbreviations AHR, airway hyper-responsiveness; BAMBI, BMP and activin membrane-bound inhibitor; BK, bradykinin; BMP, bone morphogenetic protein; CCL2/MCP-1, chemokine (CC motif) ligand 2/monocyte chemotactic protein-1; COPD, chronic obstructive pulmonary disease; CRS, chronic rhinosinusitis; CysLT, cysteinyl leukotriene; FoxP3, forkhead box P3; LAP, latency-associated protein; LTBP, latent TGF-b-binding protein; miR, microRNA; PG, prostaglandin; RORc, RAR-related orphan receptor C; TGF-b1, transforming growth factor-beta 1.Allergy 69 (2014) 699-707

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“…The observed changes in MRI signals might not have represented a therapeutic response in the mouse study, since no effect of hyaluronidase and budesonide on collagen or hydroxyproline could be observed by postmortem analyses, but it indicates that the BLM-elicited MRI signals can be modulated by hyaluronidase. Beginning the hyaluronidase treatment at an earlier timepoint after BLM, when collagen was still being deposited, as was the case in another study testing the enzyme in the murine BLM model (28), and/or by increasing the hyaluronidase dose might have resulted in an effect on collagen itself. Further investigations to explore possible therapeutic effects of hyaluronidase in the small rodent BLM models are warranted, and the herein reported signal changes provide a good basis for them.…”

Section: Discussionmentioning

confidence: 98%