What a benefit it would be to be able to replace diseased and defective heart valves with new heart valves. Thus, living tissue engineered heart valves (TEHV) would be a boon to children who require replacement heart valves that have the capacity to grow with the child and completely integrate into the child’s heart tissue. A persistent challenge for TEHV is accessible human cell source(s) that have the ability to mimic native valve cell phenotypes and possess matrix remodeling characteristics that are essential for long-term function.
Mesenchymal stem cells derived from bone marrow (BMMSC) or adipose tissue (ADMSC) are intriguing cell sources for TEHV. Unfortunately, they have not been compared to pediatric human aortic valve interstitial cells (pHAVIC) in relevant 3-dimensional culture environments.
In a recent study, Bin Duan from the Biomedical Engineering department at Cornell University compared the spontaneous and induced multipotency of ADMSC and BMMSC to that of pHAVIC using different induction culture systems within three-dimensional (3D) bioactive hybrid hydrogels that have similar material properties to those of aortic heart valve leaflets. pHAVICs possessed some multi-lineage differentiation capacity in response to induction media, but these cells were limited to the earliest stages and their differentiation capacity were less potent than either ADMSCs or BMMSCs. ADMSCs expressed cell phenotype markers that were similar to pHAVICs when they were grown in HAVIC growth media spiked with a growth factor called basic fibroblast growth factor (bFGF). BMMSCs generally expressed extra cellular matrix remodeling characteristics similar to pHAVICs.
Duan and his colleagues then chemically attached bFGF to components of the 3D hybrid hydrogels in order to further immobilize them. The immobilized bFGF upregulated vimentin expression and promoted the fibroblastic differentiation of pHAVIC, ADMSC and BMMSC. Since fibroblasts help make heart valves, these changes in gene expression might presage the ability of these cells to form new heart living heart valve tissue.
Thus, these findings show that even though mesenchymal stem cells retain a heightened capacity to form bone in 3D culture, this tendency can be shifted fibroblast cell fates by tethering bFGF to the 3-D matrix. Such a strategy is probably rather important for utilizing stem cell sources in heart valve tissue engineering applications.
This is an important finding. Even though the production of TEHVs are some ways off, Duan’s findings might provide a strategy to begin cells on the path to making TEHVs.
Joshua Hare from the Interdisciplinary Stem Cell Institute at the University of Miami Miller School of Medicine in Miami, Florida has conducted a variety of high-quality clinical trials that have tested the ability of mesenchymal stem cells to heal the hearts of patients with ischemic heart disease. Two of these trials, (Transendocardial Autologous Cells in Ischemic Heart Failure) and POSEIDON (Percutaneous Stem Cell Injection Delivery Effects on Neomyogenesis), injected mesenchymal stem cells from bone marrow directly into damaged heart muscle.
Both of these studies not only showed an increase in heart function after injection of mesenchymal stem cells compared to placebo, but further examination showed that mesenchymal stem cells induced shrinkage of the heart scar and replacement with living heart muscle tissue (see Alan Heldman and others, Transendocardial Mesenchymal Stem Cells and Mononuclear Bone Marrow Cells for Ischemic Cardiomyopathy: The TAC-HFT Randomized Trial, JAMA, Published online November 18th 2013). However, Hare wanted to compare the benefits experienced by younger patients with older patients in order to determine if age had any effect on the efficacy of this treatment.
To that end, Hare and his colleagues compared subjects from the TAC-HFT and POSEIDON clinical trials in 2 age groups: younger than 60 and 60 years of age and older. They used a 6-min walk distance to measure heart function and the Minnesota Living With Heart Failure Questionnaire (MLHFQ) to ascertain the quality of life of each patient. Patients were tested at baseline (before the procedure), 6 months, and 1 year after the procedure. Hare and his group also used particular cardiac imaging measurements, such as absolute scar size and compared the baseline size of the heart scar, and then again 1 year after the procedure.
These two tests, the 6MWD and the MLHFQ showed improvements in both age groups. These improvements were even significant in both groups. What this analyses show is that mesenchymal stem cell therapy helps patients with ischemic heart failure, regardless of their age. Older individuals did not have an impaired response to MSC therapy.
This is an important result because heart disease is very often a condition of the aged and there are concerns as to whether or not older patients would benefit from regenerative medical procedures. Hare’s study suggests that older patients do benefit from these procedures. A caveat is that older patients have lower-quality mesenchymal stem cells, but these studies tended to use allogeneic mesenchymal stem cells or stem cells from donors. Therefore, allogeneic stem cell treatments may prove effective in older heart patients.