A “sweet-spot” for fluid-induced oscillations in the conditioning of stem cell-based engineered heart valve tissues

Williams, Ann B.; Nasim, Sana; Salinas, Manuel; Moshkforoush, Arash; Tsoukias, Nikolaos M.; Ramaswamy, Sharan

doi:10.1016/j.jbiomech.2017.09.035

Cited by 10 publications

(18 citation statements)

References 21 publications

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“…It is possible that demonstration of the bone phenotype can be minimized if the specific range of pulsatile flows conducive for valvulogenesis can be identified; this range is likely to be physiologically-relevant. We were able to recently demonstrate ( 27 ) that, under a physiologically-relevant PSS condition, BMP 2 and NOTCH 1 were significantly upregulated by HBMSCs in comparison to SS-environments. There were no significant differences in the expression of the inflammatory marker VCAM and calcification-inducing TGFβ1 between the two conditions.…”

Section: Discussionmentioning

confidence: 93%

“…Specifically, on the ventricularis-side, the shear stresses are relatively higher in magnitude and uni-directional, while on the fibrosa-side, blood flow is more disturbed, resulting in lower magnitude but high-OSS. Moreover, we previously have shown that pulsatile flow leading to shear stress oscillations within a narrow physiological range augments the gene expression of several key genes of relevance to valve development ( 27 ).…”

Section: Discussionmentioning

confidence: 99%

“…A sub-set of valve-relevant genes that we previously reported on ( 12 , 27 , 34 ) were repeated for analysis in the current study after 48 h of cell culture media flow-induced shear stresses derived from a physiologically-relevant pulsatile flow waveform. A higher expression of klf2a was found in the pulsatile flow-treated HBMSCs in comparison to the SS and no flow groups.…”

Section: Discussionmentioning

confidence: 99%

“…Our laboratory has previously demonstrated that HBMSC-derived tissue formation and flow-responsive differential regulation is robust when cell-seeded constructs are cultured under fluid-induced PSS environments. Spatial distribution of HBMSCs that differentiated to the endothelial phenotype (CD31+) were largely found on the tissue surfaces, while cells with an activated myofibroblast phenotype (αSMA +) were mostly aggregated in the interstitial space, similar to the native heart valve cellular-makeup ( 12 , 13 , 26 , 27 ). Specifically, PSS regulates HBMSCs structure and has been shown to be highly relevant to both native heart valve development and to TEHVs ( 27 – 29 ).…”

Section: Introductionmentioning

confidence: 99%

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Stem Cell Cytoskeletal Responses to Pulsatile Flow in Heart Valve Tissue Engineering Studies

Castellanos

Nasim

Almora

et al. 2018

Front. Cardiovasc. Med.

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Heart valve replacement options remain exceedingly limited for pediatric patients because they cannot accommodate somatic growth. To overcome this shortcoming, heart valve tissue engineering using human bone marrow stem cells (HBMSCs) has been considered a potential solution to the treatment of critical congenital valvular defects. The mechanical environments during in vitro culture are key regulators of progenitor cell fate. Here, we report on alterations in HBMSCs, specifically in their actin cytoskeleton and their nucleus under fluid-induced shear stresses of relevance to heart valves. HBMSCs were seeded in microfluidic channels and were exposed to the following conditions: pulsatile shear stress (PSS), steady shear stress (SS), and no flow controls (n = 4/group). Changes to the actin filament structure were monitored and subsequent gene expression was evaluated. A significant increase (p < 0.05) in the number of actin filaments, filament density and angle (between 30° and 84°), and conversely a significant decrease (p < 0.05) in the length of the filaments were observed when the HBMSCs were exposed to PSS for 48 h compared to SS and no flow conditions. No significant differences in nuclear shape were observed among the groups (p > 0.05). Of particular relevance to valvulogenesis, klf2a, a critical gene in valve development, was significantly expressed only by the PSS group (p < 0.05). We conclude that HBMSCs respond to PSS by alterations to their actin filament structure that are distinct from SS and no flow conditions. These changes coupled with the subsequent gene expression findings suggest that at the cellular level, the immediate effect of PSS is to initiate a unique set of quantifiable cytoskeletal events (increased actin filament number, density and angle, but decrease in filament length) in stem cells, which could be useful in the fine-tuning of in vitro protocols in heart valve tissue engineering.

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Section: Discussionmentioning

confidence: 93%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Stem Cell Cytoskeletal Responses to Pulsatile Flow in Heart Valve Tissue Engineering Studies

Castellanos

Nasim

Almora

et al. 2018

Front. Cardiovasc. Med.

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“…Moreover, the specific nature of oscillatory flow patterns may elicit either a healthy or pathological cellular/tissue remodeling response. With our laboratory's (http://cvpeutics.fiu.edu/) emphasis in cardiovascular regenerative medicine applications, we have previously shown that specific oscillatory flow conditions (intermediate OSIs in the range of 0.18-0.23) promote the valvular phenotype in differentiating human bone marrow mesenchymal stem cells, as evidenced via gene expression results (81). Part of our on-going efforts are to assess if oscillatory flow conditions can additionally enhance the stem cell secretome, such as, for example, via exosome production for delivery of molecular factors, that could potentially enhance cardiovascular repair and regenerative processes.…”

Section: Our Laboratory's Experience In Valve Regenerative Medicinementioning

confidence: 99%

Oscillatory fluid-induced mechanobiology in heart valves with parallels to the vasculature

2020

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Forces generated by blood flow are known to contribute to cardiovascular development and remodeling. These hemodynamic forces induce molecular signals that are communicated from the endothelium to various cell types. The cardiovascular system consists of the heart and the vasculature, and together they deliver nutrients throughout the body. While heart valves and blood vessels experience different environmental forces and differ in morphology as well as cell types, they both can undergo pathological remodeling and become susceptible to calcification. In addition, while the plaque morphology is similar in valvular and vascular diseases, therapeutic targets available for the latter condition are not effective in the management of heart valve calcification. Therefore, research in valvular and vascular pathologies and treatments have largely remained independent. Nonetheless, understanding the similarities and differences in development, calcific/fibrous pathologies and healthy remodeling events between the valvular and vascular systems can help us better identify future treatments for both types of tissues, particularly for heart valve pathologies which have been understudied in comparison to arterial diseases.

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Cardiac Valve Bioreactor for Physiological Conditioning and Hydrodynamic Performance Assessment

Tefft

Choe

Young

et al. 2018

Cardiovasc Eng Tech

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Purpose: Tissue engineered heart valves (TEHV) are being investigated to address the limitations of currently available valve prostheses. In order to advance a wide variety of TEHV approaches, the goal of this study was to develop a cardiac valve bioreactor system capable of conditioning living valves with a range of hydrodynamic conditions as well as capable of assessing hydrodynamic performance to ISO 5840 standards. Methods: A bioreactor system was designed based on the Windkessel approach. Novel features including a purpose-built valve chamber and pressure feedback control were incorporated to maintain asepsis while achieving a range of hydrodynamic conditions. The system was validated by testing hydrodynamic conditions with a bioprosthesis and by operating with cell culture medium for 4 weeks and living cells for 2 weeks. Results: The bioreactor system was able to produce a range of pressure and flow conditions from static to resting adult left ventricular outflow tract to pathological including hypertension. The system operated aseptically for 4 weeks and cell viability was maintained for 2 weeks. The system was also able to record the pressure and flow data needed to calculate effective orifice area and regurgitant fraction. Conclusions: We have developed a single bioreactor system that allows for step-wise conditioning protocols to be developed for each unique TEHV design as well as allows for hydrodynamic performance assessment.

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A “sweet-spot” for fluid-induced oscillations in the conditioning of stem cell-based engineered heart valve tissues

Cited by 10 publications

References 21 publications

Stem Cell Cytoskeletal Responses to Pulsatile Flow in Heart Valve Tissue Engineering Studies

Stem Cell Cytoskeletal Responses to Pulsatile Flow in Heart Valve Tissue Engineering Studies

Oscillatory fluid-induced mechanobiology in heart valves with parallels to the vasculature

Cardiac Valve Bioreactor for Physiological Conditioning and Hydrodynamic Performance Assessment

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