Indiana Center for Vascular Biology and Medicine

Indianapolis, IN, United States

Indiana Center for Vascular Biology and Medicine

Indianapolis, IN, United States
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Murray I.R.,University of Edinburgh | Murray I.R.,Queens Medical Research Institute | Murray I.R.,University of California at Los Angeles | West C.C.,University of Edinburgh | And 13 more authors.
Cellular and Molecular Life Sciences | Year: 2014

Mesenchymal stem/stromal cells (MSCs) can regenerate tissues by direct differentiation or indirectly by stimulating angiogenesis, limiting inflammation, and recruiting tissue-specific progenitor cells. MSCs emerge and multiply in long-term cultures of total cells from the bone marrow or multiple other organs. Such a derivation in vitro is simple and convenient, hence popular, but has long precluded understanding of the native identity, tissue distribution, frequency, and natural role of MSCs, which have been defined and validated exclusively in terms of surface marker expression and developmental potential in culture into bone, cartilage, and fat. Such simple, widely accepted criteria uniformly typify MSCs, even though some differences in potential exist, depending on tissue sources. Combined immunohistochemistry, flow cytometry, and cell culture have allowed tracking the artifactual cultured mesenchymal stem/stromal cells back to perivascular anatomical regions. Presently, both pericytes enveloping microvessels and adventitial cells surrounding larger arteries and veins have been described as possible MSC forerunners. While such a vascular association would explain why MSCs have been isolated from virtually all tissues tested, the origin of the MSCs grown from umbilical cord blood remains unknown. In fact, most aspects of the biology of perivascular MSCs are still obscure, from the emergence of these cells in the embryo to the molecular control of their activity in adult tissues. Such dark areas have not compromised intents to use these cells in clinical settings though, in which purified perivascular cells already exhibit decisive advantages over conventional MSCs, including purity, thorough characterization and, principally, total independence from in vitro culture. A growing body of experimental data is currently paving the way to the medical usage of autologous sorted perivascular cells for indications in which MSCs have been previously contemplated or actually used, such as bone regeneration and cardiovascular tissue repair. © 2013 Springer.


Jensen A.R.,Indiana University | Doster D.L.,Indiana University | Hunsberger E.B.,Indiana University | Manning M.M.,Indiana University | And 8 more authors.
Shock | Year: 2016

Objective: Intestinal ischemia can quickly escalate to bowel necrosis and perforation. Transplantation of stem cells presents a novel treatment modality for this problem. We hypothesized that: human adipose-derived stromal cells (hASCs) would increase survival and mesenteric perfusion to a greater degree compared with differentiated cellular controls following ischemic intestinal injury, and improved outcomes with hASC therapy would be associated with preservation of intestinal histological and tight junction architecture, and lower levels of systemic inflammation following intestinal injury. Methods: hASCs and keratinocytes (differentiated cellular control) were cultured on polystyrene flasks at 37°C in 5% CO 2 in air. Adult male C57Bl6J mice were anesthetized and a midline laparotomy performed. The intestines were eviscerated, the small bowel mesenteric root identified, and intestinal ischemia was established by temporarily occluding the superior mesenteric artery for 60 min with a noncrushing vascular clamp. Following ischemia, the clamp was removed, and the intestines were returned to the abdominal cavity. Before abdominal closure, 2 million hASCs or keratinocytes in 250 μL of phosphate-buffered saline (carrier for cells and control solution) were infused into the peritoneum. Animals were allowed to recover for 12 or 24 h (perfusion, histology, cytokine, and immunofluoresence studies), or 7 days (survival studies). Intestinal perfusion was assessed by laser Doppler imaging. Intestinal tissue segments were stained with hematoxylin and eosin, as well as antibodies for the tight junction protein claudin-1. Separate aliquots of intestine, liver, and lung tissue were homogenized and assessed for inflammatory cytokines via multiplex beaded assay. Results: Animals administered hASCs following intestinal ischemia and reperfusion (I/R) injury had significantly greater 7-day survival and better postischemic recovery of mesenteric perfusion compared with vehicle or keratinocyte therapy. hASCs also abated intestinal mucosal destruction, facilitated preservation of intestinal tight junctions, and decreased the systemic inflammatory response to injury. Conclusions: Human adipose-derived stromal cells improved survival and mesenteric perfusion and attenuated the mucosal damage associated with intestinal I/R injury. hASCs should be considered as a plausible cell source for novel cellular treatment plans following intestinal ischemia. © 2016 by the Shock Society.


Dai J.,Indiana University Bloomington | Dai J.,Indiana Center for Vascular Biology and Medicine | Dai J.,Indiana University | Lampert R.,Yale University | And 4 more authors.
Circulation: Cardiovascular Quality and Outcomes | Year: 2010

Background-Reduced heart rate variability (HRV), a measure of cardiac autonomic dysfunction, is a risk factor for coronary artery disease. Diet can influence HRV, but this association may be confounded by genetic and environmental factors. Methods and Results-We administered the Willett Food Frequency Questionnaire to 276 middle-aged male twins. We derived a score measuring the extent to which an individual's diet conformed to the Mediterranean diet following a published algorithm. The higher the score, the greater the similarity to the Mediterranean diet. All twins underwent 24-hour ambulatory ECG recording. Time and frequency domain measures of HRV were calculated. Mixed-effects regression was used to partition the association into between- and within-twin pair differences. After adjusting for energy intake, other nutritional factors, shared genes, and common environment, a 1-unit higher score was significantly associated with 3.9% to 13% higher time and frequency domain HRV parameters. Further controlling for known cardiovascular risk factors and use of fish oil supplements and medications did not substantially change the estimates. Conclusions-The Mediterranean dietary pattern is associated with higher HRV. © 2010 American Heart Association, Inc.


Kamocka M.M.,Indiana University | Kamocka M.M.,Indiana Center for Vascular Biology and Medicine | Mu J.,University of Notre Dame | Liu X.,University of Notre Dame | And 10 more authors.
Journal of Biomedical Optics | Year: 2010

Thrombus development in mouse mesenteric vessels following laser-induced injury was monitored by high-resolution, near-real-time, two-photon, intravital microscopy. In addition to the use of fluorescently tagged fibrin(ogen) and platelets, plasma was labeled with fluorescently tagged dextran. Because blood cells exclude the dextran in the single plane, blood cells appear as black silhouettes. Thus, in addition to monitoring the accumulation of platelets and fibrin in the thrombus, the protocol detects the movement and incorporation of unlabeled cells in and around it. The developing thrombus perturbs the blood flow near the thrombus surface, which affects the incorporation of platelets and blood cells into the structure. The hemodynamic effects and incorporation of blood cells lead to the development of thrombi with heterogeneous domain structures. Additionally, image processing algorithms and simulations were used to quantify structural features of developing thrombi. This analysis suggests a novel mechanism to stop the growth of developing thrombus. © 2010 Society of Photo-Optical Instrumentation Engineers.


Merfeld-Clauss S.,Indiana Center for Vascular Biology and Medicine | Merfeld-Clauss S.,Center for Regenerative Medicine | Lupov I.P.,Indiana Center for Vascular Biology and Medicine | Lupov I.P.,Center for Regenerative Medicine | And 11 more authors.
Circulation Research | Year: 2014

Rationale: Adipose stromal cells (ASC) are therapeutically potent progenitor cells that possess properties of pericytes. In vivo, ASC in combination with endothelial cells (EC) establish functional multilayer vessels, in which ASC form the outer vessel layer and differentiate into mural cells. Objective: To identify factors responsible for ASC differentiation toward the smooth muscle cell phenotype via interaction with EC. Methods and Results: An in vitro model of EC cocultivation with ASC was used, in which EC organized into vascular cords, accompanied by ASC migration toward EC and upregulation of α-smooth muscle actin, SM22α, and calponin expression. Conditioned media from EC-ASC, but not from EC cultures, induced smooth muscle cell protein expression in ASC monocultures. EC-ASC cocultivation induced marked accumulation of activin A but not transforming growth factor-β1 in conditioned media. This was attributed to induction of activin A expression in ASC on contact with EC. Although transforming growth factor-β and activin A were individually sufficient to initiate expression of smooth muscle cell antigens in ASC, only activin A IgG blocked the effect of EC-ASC conditioned media. Although transforming growth factor-β was able to induce activin A expression in ASC, in cocultures this induction was transforming growth factor-β independent. In EC-ASC cocultures, activin A IgG or ALK4/5/7 receptor inhibitors blocked expression of α-smooth muscle actin in ASC in the absence of direct ECcord contact, but this inhibition was circumvented in ASC by direct EC contact. Conclusions: EC initiate a smooth muscle cell differentiation program in adjacent ASC and propagate this differentiation in distant ASC by induction of activin A expression. (Circ Res. 2014;115:800-809.) © 2014 American Heart Association, Inc.


PubMed | Center for Regenerative Medicine and Indiana Center for Vascular Biology and Medicine
Type: | Journal: Journal of tissue engineering and regenerative medicine | Year: 2016

Adipose stromal cells (ASCs) support endothelial cell (EC) vasculogenesis through paracrine and cell-contact communications. In addition, ASCs differentiate towards the smooth muscle cell (SMC) phenotype under different stimuli, which prompted their use as a source of mural cells in fabricating small calibre vessels. How ASCs SMC-lineage commitment affects their subsequent communication with ECs is unknown. The vasculogenic characteristics of human ASCs in progenitor stage and after differentiation towards SMC phenotype were analysed in the present study. Exposure to transforming growth factor 1 (TGF


Hong S.J.,Krannert Institute of Cardiology | Hong S.J.,Indiana Center for Vascular Biology and Medicine | Hong S.J.,Indiana University | Hong S.J.,Korea University | And 7 more authors.
Current Opinion in Organ Transplantation | Year: 2010

Purpose of review: Adipose-derived stem cells (ASCs) are readily available from autologous adipose tissue and have been demonstrated to provide significant potential for tissue rescue from, or repair of, damage in multiple animal models. These include models of myocardial infarction, heart failure, hind limb ischemia, and inflammatory conditions. Early clinical studies have now extended testing of the effects of ASC into patients. This review highlights some of the key reports underlining the potential of ASCs, focusing particularly on diseases involving the cardiovascular system, vascular growth, and tissue repair. Recent findings: Clinical applications of ASCs have begun to show early safety results and promising possibility of efficacy in patients with a range of diseases, including acute myocardial infarction, peripheral vascular disease, and soft and bony tissue defects including cranial bone loss, Crohn's-related fistula, and skin wounds. These effects are importantly based on the secretion of trophic and survival factors by these cells and by their participations in the growth and remodeling of blood vessels. These results suggest that ASCs could be a valuable therapeutic option in vascular growth and tissue repair in various clinical settings. Summary: ASCs may ultimately represent a valuable therapeutic option in tissue rescue and repair based on their ready availability, proangiogenesis and antiapoptotic factor secretion, immunomodulatory effects, and capacity for multilineage differentiation and ready expansion. © 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins.


Dai J.,Vanderbilt University | Dai J.,Indiana University Bloomington | Dai J.,Indiana Center for Vascular Biology and Medicine | Krasnow R.E.,SRI International | And 3 more authors.
PLoS ONE | Year: 2013

Background:Due to the paucity of direct evidence, we aimed to evaluate whether the association between postload plasma glucose levels (ppGlucose) and long-term risk of mortality from coronary heart disease was independent of or attributable to genes and common environment.Methods and Findings:From the prospective National Heart, Lung, and Blood Institute (NHLBI) Twin Study, we included 903 middle-aged male twins, who were nondiabetic, free of coronary heart disease at baseline (1969-1973), and followed for up to 38 years for coronary heart, cardiovascular, and all-cause mortality. Frailty survival models were used to estimate hazard ratio (HR) for various associations: overall (equivalent to singleton population association), within-pair (controlling for genes and environment common to co-twins), and between-pair association (reflecting influences of common factors). Overall associations were statistically significant for coronary heart and cardiovascular but not all-cause deaths after controlling for known risk factors. The associations were not statistically significant in within-pair analyses. The within-pair association was not statistically different by zygosity for specific and all-cause death risk. After the full adjustment for known risk factors, HR (95% confidence interval) for within-pair association was 1.07 (0.90, 1.28), 1.06 (0.94, 1.19), and 0.99 (0.94, 1.05) for coronary heart, cardiovascular, and all-cause mortality, respectively. The fully adjusted between-pair associations were statistically significant for specific and all-cause death risk: a 50 mg/dL increase in the mean value of ppGlucose for a twin pair was associated with a raised death risk [HR (95% confidence interval) 1.15 (1.02, 1.30), 1.10 (1.02, 1.20), and 1.05 (1.01, 1.09) for coronary heart, cardiovascular, and all-cause mortality, respectively]. Between-pair association was significant in dizygotic but not in monozygotic twins.Conclusion:The positive association between ppGlucose and long-term coronary heart mortality risk is largely explained by factors shared between co-twins, including familial factors; however, within-pair effects cannot be absolutely excluded. © 2013 Dai et al.


Hadad I.,Indiana University | Johnstone B.H.,Indiana Center for Vascular Biology and Medicine | Brabham J.G.,Indiana University | Blanton M.W.,Indiana University | And 8 more authors.
International Journal of Radiation Oncology Biology Physics | Year: 2010

Purpose: A delayed full-thickness wound-healing model was developed and used for examining the capacity of adipose-derived stem cells (ASCs), either alone or in platelet-rich fibrin gels, to promote healing. Methods and Materials: Four pigs received electron beam radiation to the dorsal skin surface. Five weeks after radiation, subcutaneous fat was harvested from nonirradiated areas and processed to yield ASCs. Two weeks later, 28 to 30 full-thickness 1.5-cm2 wounds were made in irradiated and nonirradiated skin. Wounds were treated with either saline solution, ASCs in saline solution, platelet-rich plasma (PRP) fibrin gel, ASCs in PRP, or non-autologous green fluorescence protein-labeled ASCs. Results: The single radiation dose produced a significant loss of dermal microvasculature density (75%) by 7 weeks. There was a significant difference in the rate of healing between irradiated and nonirradiated skin treated with saline solution. The ASCs in PRP-treated wounds exhibited a significant 11.2% improvement in wound healing compared with saline solution. Enhancement was dependent on the combination of ASCs and PRP, because neither ASCs nor PRP alone had an effect. Conclusions: We have created a model that simulates the clinically relevant late radiation effects of delayed wound healing. Using this model, we showed that a combination of ASCs and PRP improves the healing rates of perfusion-depleted tissues, possibly through enhancing local levels of growth factors. © 2010 Elsevier Inc. All rights reserved.


PubMed | Indiana University, Indiana Center for Vascular Biology and Medicine and University of Wisconsin - Madison
Type: Journal Article | Journal: American journal of physiology. Lung cellular and molecular physiology | Year: 2016

17-Estradiol (E2) exerts protective effects on right ventricular (RV) function in pulmonary arterial hypertension (PAH). Since acute exercise-induced increases in afterload may lead to RV dysfunction in PAH, we sought to determine whether E2 allows for superior RV adaptation after an acute exercise challenge. We studied echocardiographic, hemodynamic, structural, and biochemical markers of RV function in male and female rats with sugen/hypoxia (SuHx)-induced pulmonary hypertension, as well as in ovariectomized (OVX) SuHx females, with or without concomitant E2 repletion (75 gkg(-1)day(-1)) immediately after 45 min of treadmill running at 75% of individually determined maximal aerobic capacity (75% aerobic capacity reserve). Compared with males, intact female rats exhibited higher stroke volume and cardiac indexes, a strong trend for better RV compliance, and less pronounced increases in indexed total pulmonary resistance. OVX abrogated favorable RV adaptations, whereas E2 repletion after OVX markedly improved RV function. E2s effects on pulmonary vascular remodeling were complex and less robust than its RV effects. Postexercise hemodynamics in females with endogenous or exogenous E2 were similar to hemodynamics in nonexercised controls, whereas OVX rats exhibited more severely altered postexercise hemodynamics. E2 mediated inhibitory effects on RV fibrosis and attenuated increases in RV collagen I/III ratio. Proapoptotic signaling, endothelial nitric oxide synthase phosphorylation, and autophagic flux markers were affected by E2 depletion and/or repletion. Markers of impaired autophagic flux correlated with endpoints of RV structure and function. Endogenous and exogenous E2 exerts protective effects on RV function measured immediately after an acute exercise challenge. Harnessing E2s mechanisms may lead to novel RV-directed therapies.

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