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Pathologic bladder microenvironment attenuates smooth muscle differentiation of skin derived precursor cells: implications for tissue regeneration.

ABSTRACT: Smooth muscle cell containing organs (bladder, heart, blood vessels) are damaged by a variety of pathological conditions necessitating surgery or organ replacement. Currently, regeneration of contractile tissues is hampered by lack of functional smooth muscle cells. Multipotent skin derived progenitor cells (SKPs) can easily be isolated from adult skin and can be differentiated in vitro into contractile smooth muscle cells by exposure to FBS. Here we demonstrate an inhibitory effect of a pathologic contractile organ microenvironment on smooth muscle cell differentiation of SKPs. In vivo, urinary bladder strain induces microenvironmental changes leading to de-differentiation of fully differentiated bladder smooth muscle cells. Co-culture of SKPs with organoids isolated from ex vivo stretched bladders or exposure of SKPs to diffusible factors released by stretched bladders (e.g. bFGF) suppresses expression of smooth muscle markers (alpha SMactin, calponin, myocardin, myosin heavy chain) as demonstrated by qPCR and immunofluorescent staining. Rapamycin, an inhibitor of mTOR signalling, previously observed to prevent bladder strain induced de-differentiation of fully differentiated smooth muscle cells in vitro, inhibits FBS-induced smooth muscle cell differentiation of undifferentiated SKPs. These results suggest that intended precursor cell differentiation may be paradoxically suppressed by the disease context for which regeneration may be required. Organ-specific microenvironment contexts, particularly prevailing disease, may play a significant role in modulating or attenuating an intended stem cell phenotypic fate, possibly explaining the variable and inefficient differentiation of stem cell constructs in in vivo settings. These observations must be considered in drafting any regeneration strategies.

SUBMITTER: Tolg C

PROVIDER: S-EPMC3613403 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Pathologic bladder microenvironment attenuates smooth muscle differentiation of skin derived precursor cells: implications for tissue regeneration.

Tolg Cornelia C Ahsan Alya A Dworski Shaalee S Kirwan Tyler T Yu Jeffery J Aitken Karen K Bägli Darius Jehan DJ

PloS one 20130401 4

Smooth muscle cell containing organs (bladder, heart, blood vessels) are damaged by a variety of pathological conditions necessitating surgery or organ replacement. Currently, regeneration of contractile tissues is hampered by lack of functional smooth muscle cells. Multipotent skin derived progenitor cells (SKPs) can easily be isolated from adult skin and can be differentiated in vitro into contractile smooth muscle cells by exposure to FBS. Here we demonstrate an inhibitory effect of a patholo ...[more]

PMID: 23560047

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Project description:PurposeTo test the hypothesis that bladder preservation therapy consisting of definitive chemoradiotherapy (chemoRT) results in similar overall survival rates to radical cystectomy/chemotherapy when balancing baseline patient characteristics and initial (preoperative) clinical stage.Materials/methodsA total of 7,322 patients with stage II-IV, M0 bladder cancer who were treated with cystectomy/chemo (N = 5,664) or definitive chemoRT (N = 1,658) were identified from the National Cancer Database. Baseline patient characteristics were compared using Pearson's chi-square, Fisher's exact test, and Wilcoxon's rank sum tests. Cox regressions were used to investigate for variables significantly correlated with overall survival (OS). OS was compared between cystectomy/chemo vs chemoRT before and after propensity score matched pair analyses using Kaplan-Meier curves and log-rank tests.ResultsPatients who underwent cystectomy/chemo were significantly younger than ones treated with definitive chemoRT (mean age 63.7 vs 75.2; P < 0.001). Age, race, Charlson/Deyo Comorbidity Score (CDCS), clinical stage, insurance status, and type of facility significantly correlated with OS (P < 0.05 for all covariates). Patients treated with cystectomy/chemo were younger, healthier with better CDCS, and more likely treated at academic facilities. Before matched pair analyses, OS was significantly better when treated with cystectomy/chemo (3 year 56.4%; 5 year 45.9%) compared to chemoRT (3 year 47.3%; 5 year 33.2%) (P < 0.001); 28.6% of patients undergoing cystectomy were upstaged at the time of surgery. After matched pair analyses matching age, race, sex, CDCS, clinical (presurgical) stage, insurance, and facility type (N = 1,750), OS was no longer significantly different between cystectomy/chemo (3 year 52.1% and 5 year 41.0%) vs chemoRT (3 year 53.3% and 5 year 40.1%) (P = 0.5).ConclusionsPatients treated with cystectomy/chemo were significantly younger and healthier compared to those treated with chemoRT. Once these factors were accounted for in propensity score matched pair analyses using clinical stage, overall survival was not significantly different between cystectomy/chemo and an organ-sparing approach with definitive chemoRT.

Project description:RationaleVascular calcification is a prominent feature of late-stage diabetes, renal and cardiovascular disease (CVD), and has been linked to adverse events. Recent studies in patients reported that plasma levels of osteomodulin (OMD), a proteoglycan involved in bone mineralisation, associate with diabetes and CVD. We hypothesised that OMD could be implicated in these diseases via vascular calcification as a common underlying factor and aimed to investigate its role in this context.Methods and resultsIn patients with chronic kidney disease, plasma OMD levels correlated with markers of inflammation and bone turnover, with the protein present in calcified arterial media. Plasma OMD also associated with cardiac calcification and the protein was detected in calcified valve leaflets by immunohistochemistry. In patients with carotid atherosclerosis, circulating OMD was increased in association with plaque calcification as assessed by computed tomography. Transcriptomic and proteomic data showed that OMD was upregulated in atherosclerotic compared to control arteries, particularly in calcified plaques, where OMD expression correlated positively with markers of smooth muscle cells (SMCs), osteoblasts and glycoproteins. Immunostaining confirmed that OMD was abundantly present in calcified plaques, localised to extracellular matrix and regions rich in α-SMA+ cells. In vivo, OMD was enriched in SMCs around calcified nodules in aortic media of nephrectomised rats and in plaques from ApoE-/- mice on warfarin. In vitro experiments revealed that OMD mRNA was upregulated in SMCs stimulated with IFNγ, BMP2, TGFβ1, phosphate and β-glycerophosphate, and by administration of recombinant human OMD protein (rhOMD). Mechanistically, addition of rhOMD repressed the calcification process of SMCs treated with phosphate by maintaining their contractile phenotype along with enriched matrix organisation, thereby attenuating SMC osteoblastic transformation. Mechanistically, the role of OMD is exerted likely through its link with SMAD3 and TGFB1 signalling, and interplay with BMP2 in vascular tissues.ConclusionWe report a consistent association of both circulating and tissue OMD levels with cardiovascular calcification, highlighting the potential of OMD as a clinical biomarker. OMD was localised in medial and intimal α-SMA+ regions of calcified cardiovascular tissues, induced by pro-inflammatory and pro-osteogenic stimuli, while the presence of OMD in extracellular environment attenuated SMC calcification.

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Pathologic bladder microenvironment attenuates smooth muscle differentiation of skin derived precursor cells: implications for tissue regeneration.

Publications

Pathologic bladder microenvironment attenuates smooth muscle differentiation of skin derived precursor cells: implications for tissue regeneration.

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