Stem cell therapy for the heart: hype or hope?

STEM cell treatment continues to be bandied around as the "magic " bullet for many health conditions. It is time to take stock of the state of technology concerning the use of stem cells in heart disease

The normal heart cell

The first thing we need to understand is how our heart grows or renews itself. During the early stages of development as a foetus, the heart grows by increasing the absolute number of heart cells . As we grow, the main mechanism of growth of the heart is an increase in the size of the heart cell. In the healthy, uninjured adult human heart, the total number of heart cells remains largely unchanged.

Current evidence suggests that the renewal of heart cells derives from a modest level of pre-existing proliferation of heart cells. There are early stem cells residing in the heart but their contribution under basal conditions or after injury is low (estimated to be at a rate of <0.01 per cent per year).

Annual human heart cell turnover rates over lifespan are calculated to be 1.9 per cent (adolescent), 1 per cent (middle age), and 0.45 per cent (old age), and by age 50 the heart cells remaining from birth are about 55 per cent, whereas 45 per cent are generated later in life.

Renewal of heart cells

After the heart is injured, the rate of renewal of the heart cells may be higher than under normal conditions. Most studies suggest that the infusion, injection, or tissue-based implantation of cells of various origins, commonly referred to as stem cell therapy, confers beneficial effects to the injured heart. These stem cell therapies may promote the existing heart cell renewal or generate new heart cells from the transplanted stem cells. The degree of new heart cell formation is dependent on the source of the cell and the ability of these stem cells to survive and remain within the heart.

One hour after the infusion of stem cells into the heart arteries, the retention of unselected bone marrow derived stem cells in the heart is low; a rate of <3 per cent for unselected bone marrow cells. For selected bone marrow stem cells which carry a protein, CD34 , on its surface, this retention can increase about tenfold. CD34 is a protein on the surface of some cells and it facilitates the migration of cells. This percentage of retention may be higher if the stem cells were directly injected into the heart muscle.

Discordance

The extent of the renewal of the heart cells either by promoting heart cell renewal or transformation of the transplanted stem cells into new heart cells cannot explain the extent of functional improvement of the heart. Hence, researchers have suggested that there are other mechanisms that account for at least part of the beneficial effects of cell therapy.

It has been shown that transplantation of heart cells derived from early stem cells can generate new heart muscle that beats in synchrony with the pre-existing heart muscle and may contribute to heart pump function, although the extent of this contribution has not been determined.

While these results suggest benefit, the real functional improvement in the heart is very modest and may not translate into real benefits. More trials are under way to determine the clinical benefit of stem cell therapy.

Type of stem cells

Different stem cells have different outcomes. The first group of cells that are used are bone marrow-derived cells. Stem cells that are derived directly from bone marrow without further separation into different cell populations do not appear to become heart muscle cells when infused or injected into heart arteries.

Certain types of bone marrow-derived cell populations such as c-kit+ cells or mesenchymal stem cells may promote the renewal of heart cells through indirect biological actions. Early studies with these mesenchymal stem cells have been promising and advanced (phase 3) trials are under way. It is uncertain what eventually happens to these mesenchymal stem cells although some studies suggest that these cells can transform into heart cells at a low rate.

The second type of cells are stem cells derived from the heart. These cells which include c-kit+ cells, cardiosphere-derived cells, or Sca1+ cells, are obtained from tissue specimens obtained by biopsy of the heart tissue and subsequently isolating the cells. These cells are then grown in the laboratory. The functional improvement seen after the delivery of these cells into the heart cannot be explained by new heart cell formation alone. In any case, the new heart cell formation is very low.

The third type of stem cell used are the pluripotent stem cells (embryonic stem cells or induced pluripotent stem cells) which can continue to multiply in an early stem cell form and on exposure to certain biological agents, can transform into almost any cell, including heart muscle cells.

In laboratory cultures, the transformation of pluripotent stem cells into early heart cells can exceed 80 per cent. Pluripotent stem cell-derived heart cells generate new heart muscle when injected into the injured or uninjured heart of immuno-suppressed animals. Long-term retention and survival of these cells beyond three months has not been studied. These new heart cells can contract in synchrony with pre-existing heart muscle. An important risk is an increased incidence of developing abnormal heart rhythms.

The new heart muscle can explain some but not all of the functional improvements. Despite these promising benefits, there is concern that tumours (teratomas) can form when such cells are injected into the heart of immunocompromised organisms.

The future of stem cells

Before we rejoice at the published results of studies, we need to understand that these studies are small studies which have demonstrated a statistically significant functional benefit. However, these results have yet to be translated to a significant functional benefit in the real world setting. The main reason is that most of the stem cells that are being transplanted do not survive.

While laboratory studies suggest that some types of stem cells may be better than others , it has been difficult to determine which is the most effective cell type as very small numbers of cells survive and engraft into the heart muscle.

Hence, there are many ongoing studies to determine the best way to protect the stem cells and ensure their survival during the delivery of these stem cells into the heart muscle.

Other methods involve the use of biological scaffolds which provide a more conducive environment for the stem cells to survive and engraft onto the heart muscle. Hence, for stem cell therapy to be effective in the real world situation, better delivery platforms need to be developed to ensure survival of the majority of these stem cells. The good news is that there is light at the end of tunnel.

This series is produced on alternate Saturdays in collaboration with Singapore Heart, Stroke and Cancer Centre.