Future prospects in the tissue engineering of heart valves: a focus on the role of stem cells

ABSTRACT

Introduction

Heart valve disease is a growing burden on the healthcare system. Current solutions are insufficient for young patients and do not offer relief from reintervention. Tissue engineered heart valves (TEHVs) offer a solution that grows and responds to the native environment in a similar way to a healthy valve. Stem cells hold potential to populate these valves as a malleable source that can adapt to environmental cues.

Areas covered

This review covers current methods of recapitulating features of native heart valves with tissue engineering through use of stem cell populations with in situ and in vitro methods.

Expert opinion

In the field of TEHVs, we see a variety of approaches in cell source, biomaterial, and maturation methods. Choosing appropriate cell populations may be very patient specific; consistency and predictability will be key to long-term success. In situ methods are closer to translation but struggle with consistent cellularization. In vitro culture requires specialized methods but may recapitulate native valve cell populations with higher fidelity. Understanding how cell populations react to valve conditions and immune response is vital for success. Detrimental valve pathologies have proven to be difficult to avoid in early translation attempts.

KEYWORDS:

• Tissue engineered heart valves (TEHV)
• stem cells
• biomaterials
• valvular endothelial cells (VEC)
• valvular interstitial cells (VIC)

Article highlights

• Valvular heart disease represents a large burden to the global healthcare system and tissue engineered heart valves (TEHVs) may offer a permanent solution for young patients. TEHVs that are made of cellularized biomaterials may be able to grow and maintain throughout a lifetime and should recapitulate native valve composition and function modulated by cells populating the TEHV.

• Stem cells and other progenitor cells are cell populations that may be able to replicate the function and behavior of native valve cells and differentiate into stable valve phenotypes. However, matching cellularization technique with patient-specific needs and predicted outcomes will be vital to the future of research in this field.

• In vitro culture methods of TEHVs offer control over the cellularization and development of the tissue. Embedding or surface seeding of stem cells onto in vitro valves allows for command of the differentiation process toward valve-like populations through mechanical and biochemical cues. Successful clinical translation of these methods will require optimal conditioning parameters and determination of patient reaction to implantation based on material and cell type.

• In situ TEHV methods provide the opportunity for a more ‘off-the-shelf’ solution as an acellular material. In situ valves can immediately function in hemodynamic conditions but offer less control over the cellularization process. Biomaterial selection and coating the valves with signaling factors can enhance the cellularization of progenitor and stem cell populations, but predicting both short- and long-term immune reaction has been difficult.

• Reproducibility with stem cells on a clinically translatable scale is a major concern in terms of maintaining healthy, non-pathological phenotypes in valve development. Ensuring consistent phenotypic differentiation in TEHVs will be the most important goal for determining TEHV cell sources, biomaterials, and conditioning methods.

Acknowledgments

Figures 1-4 were created with BioRender.com.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was funded by the National Science Foundation Graduate Research Fellowship (DGE-1650441), National Institutes of Health R01 HL151190 and R01 HL143247.