RSC Advances Blog

Hair and nails grow back, but heart valves cannot regenerate naturally. This fact is being challenged by a team of scientists who have developed a method that could someday regrow defective heart valves.

Valvular interstitial cells (VIC), the most prevalent cells in the heart valve, are developmentally locked in a state of quiescence, preventing their division within the body. In people suffering from inflammation-induced or inborn heart valve defects, damaged valves have to be replaced surgically with either mechanical (made with artificial polymers) or bioprosthetic (made with heart tissue) valves.

People with artificial valves are required to take blood thinners for extended periods and make significant changes to their lifestyle. In addition, artificial valves in younger patients do not grow and remodel with time, causing additional complications during adulthood. These issues are further compounded by an estimate suggesting that over 850,000 patients will require heart valve transplants by the year 2050.

Soumen Jana and colleagues at the Division of Cardiovascular Diseases, Mayo Clinic, USA approached this problem from a different angle. Relying on studies showing that VICs can be isolated from heart valves and grown in a laboratory setting, the team developed a nanofibrous membrane-based scaffolding structure to support the growth of VICs. Similar to the cross-cross patterns formed by ropes in a hammock, their polycaprolactone polymer scaffold comprises randomly oriented nanofibers (~457 nm in diameter) to form a cradle within which VICs from defective valves can be grown.

Within the body, VICs are arranged as monolayer sheets, forming a veneer on the outer surfaces of heart valve leaflets. They form this complex structure by depositing collagen – a cellular cementing protein that allows cells to interlock like a cobblestone path to form a sheet-like structure. The researchers reasoned that by artificially simulating conditions ideal for VIC growth within the body, they could create VIC sheets in the laboratory and examine their similarity to naturally occurring VICs in heart valve leaflets.

The study found that VICs from healthy valves showed greater levels of cell division on the scaffold compared to VICs from defective valves. Interestingly, the scaffold induced collagen deposition from VICs obtained from both healthy and defective valves. The study also looked at a series of genes and proteins important in VIC growth. Patient derived VICs grown on nanofibrous scaffolds deposited appropriate amounts of cementing proteins necessary for leaflet regeneration.

Clinical trials aimed at regenerating heart valves with chemical drugs and DNA modifying methods are under way. In their study, Jana and colleagues suggest VIC regeneration as a novel idea. They also engineer a scaffold that supports VIC growth, demonstrate its practicality and highlight its ability to be translated into a clinically impactful technology.

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Regeneration ability of valvular interstitial cells from diseased heart valve leaflets
Soumen Jana, Rebecca Hennessy, Federico Franchi, Melissa Young, Ryan Hennessya and Amir Lerman

Paclitaxel (PTX) is among the most widely used chemotherapeutic agents in clinical settings. The drug imposes its anticancer effect by preventing cell division. Cancer cells learn to resist PTX over time by various mechanisms including creating alterations in the protein targeted by PTX and rewiring of cell survival pathways to evade cell death.

Clinicians combine PTX with suberoylanilide hydroxamic acid (SAHA) to suppress cancer drug resistance and improve treatment outcome. The benefits of combination therapy include improved accumulation of the drug at cancer sites, the ability to trigger cell death by complementary or synergistic mechanisms and longer retention of the drug within patients. Given the strong rationale for combination therapies, Shu and colleagues at the Department of Pharmaceutical Analysis, Key Laboratory on Protein Chemistry and Structural Biology, China developed a novel peptide hydrogel which encapsulates PTX and SAHA within a single co-delivery nano-carrier.

The researchers loaded PTX and SAHA onto the same nano-carrier in the following sequence: (1) an amino acid-based self assembling hydrogel precursor (Nap) was prepared, (2) PTX was conjugated to the self assembling hydrogel to form a pro-drug and (3) the pro-drug was allowed to encapsulate SAHA, forming the final drug (Nap-PTX-SAHA). The researchers subsequently characterized the mechanical features of their novel drug delivery system and tested it using a mouse model of liver cancer.

The study found that the Nap-PTX-SAHA hydrogels could be injected at room temperature into test mice, suggesting that no specialized equipment or storage conditions were necessary to administer the drug. The study also found that SAHA is released more readily than PTX from Nap-PTX-SAHA hydrogels. This could mean that cancer cells will be exposed to the two chemotherapy agents at different times, allowing for a one-two punch based tumor killing strategy.

When administered to tumor-bearing mice, the Nap-PTX-SAHA regimen was found to decrease tumor volume up to 2-fold compared to mice treated traditionally with PTX or SAHA alone. Interestingly, the researchers also noted that Nap-PTX-SAHA was associated with fewer side effects, as evidenced by normal eating behavior and weight in test mice. Interestingly, Nap-PTX-SAHA was absorbed lesser in non-target organs such as the heart, spleen and kidneys.

On the basis of these promising preclinical studies, the authors propose that Nap-PTX-SAHA represents a promising candidate for clinical trials in the years to come.

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