Stem Cell Dormancy Enables Them to Remain Viable Days After Death

A collaboration of several researchers from French Institutions has demonstrated that humans and mouse stem cells have the ability to become dormant when their environment becomes hostile, including several days after the death of the organism. This ability to significantly reduce metabolic activity enables them to preserve their potential for cellular division, even a long time after death. Once isolated from the cadaver, the stem cells retain their healing abilities. This discovery could be the beginning of new therapeutic avenues for treating numerous diseases.

Skeletal muscle stem cells have the ability to survive for seventeen days in humans and sixteen days in mice, after death. This discovery was made by researchers from the Institut Pasteur, the Université de Versailles Saint-Quentin-en-Yvelines, the Paris Public Hospital Network (AP-HP), and the CNRS under the direction of Professor Fabrice Chrétien, in collaboration with a team led by Professor Shahragim Tajbakhsh. These laboratories showed that once the stem cells from the cadavers were grown in culture, they retained their capacity to differentiate into perfectly functioning muscle cells.

Once they made this surprising discovery, the next step was to determine precisely how these cells survive such adverse conditions. As it turns out, the stem cells enter a deeper state of sleep (quiescence), and this drastically lowers their metabolism. This so-called “dormant” state results from stripping the functional structures of the cell to their bare minimum. For example, these cells have fewer mitochondria (cellular power plants using oxygen to produce energy in cells) and diminished stores of energy.

Fabrice Chrétien explained it this way: “We can compare this to pathological conditions where cells are severely deficient in resources, before regaining a normal cell cycle for regenerating damaged tissues and organs. When muscle is in the acute phase of a lesion, the distribution of oxygen is highly disrupted. We have even observed that muscle stem cells in anoxia (totally deprived of oxygen) at 4°C have a better survival rate than those regularly exposed to ambient levels of oxygen.”

Chrétien’s team wondered if other cell types showed similar capacities. Once again, the results were surprising. Stem cells from bone marrow where blood remained viable for four days after death in mice. More importantly, they retained their ability to reconstitute tissue after a bone marrow transplant.

This discovery could form the basis of a new source, and more importantly new methods of conservation, for those stem cells used to treat different conditions. For example, leukemia treatments require a bone marrow transplant to restore those blood and immune cells that were destroyed by chemotherapy and radiation. By harvesting stem cells from the bone marrow of consenting donors after death, doctors could address to some extent, the shortage of tissues and cells. Although highly promising, this approach in the realm of cellular therapy still requires more testing and validation before it can be used in clinical applications. However, it paves the way to investigate the viability of stem cells from all tissues and organs post-mortem.

Reprogramming Heart Fibroblasts into Heart Muscle Cells Goes to Human Trials

Last month, this blog reported on the conversion of heart-based fibroblasts into heart muscle cells after a heart attack in living, laboratory animals by means of gene therapy. Another researcher has utilized a different strategy to achieve the same result. This work has also provided the means for biotechnology companies to begin clinical trials using this very strategy.

Scar formation (fibrosis), prevents the regeneration of heart muscle and creates a scar that does not contract. The loss of contractile function leads to heart failure and death. Therapeutic goals for these conditions include limiting scar formation.

To that end, Eric C. Olson and his colleagues from UT Southwestern were able to introduce four genes (GATA4, HAND2, MEFC2, and TBX5) into heart-based fibroblasts and convert them into beating heart muscle cells. To do this, Olson and his army of graduate students, technicians, and postdoctoral research fellows made genetically engineered viruses that encoded the four genes (collective known as GHMT).  When the GHMT-viruses were injected into mouse hearts after a heart attack, the four genes reprogrammed the fibroblasts into heart muscle cells in tissue culture and inside living animals.  Furthermore, when GHMT is introduced into fibroblasts after a heart attack, the fibroblasts do not make scar tissue, but heart muscle.

Olson and his team also used techniques that allowed them to trace cells and their descendents.  These techniques showed that the heart muscle that formed after the heart attack were the result of cells that had been infected by the engineered viruses (that is, they contained viral DNA).  Thus the new heart muscle came about because the virally-infected fibroblasts turned into heart muscle that began to beat.  Also, heart imaging also showed that infection of the heart with GHMT viruses greatly boosted heart function after a heart attack in comparison to control heart that were infected by the viruses that did not contain GHMT.

Can such a technology make it way to clinical trials?  Fortunately, Eric Olson is not only chairman of the Molecular Biology department as UT Southwestern, but he is also co-founder of a medical technology company known as LoneStar Heart Inc.  Olson’s company hopes to extend his findings in laboratory animals and eventually gain approval to begin human clinical trials.  Olson noted, “These studies establish proof-of-concept for in vivo cellular reprogramming as a new approach for heart repair. However, much work remains to be done to determine if this strategy might eventually be effective in humans. We are working hard toward that goal.”

LoneStar Heart is capitalizing on previous work by Olson and others in his laboratory that have established that the delivery of the four previously mentioned genes increases heart regeneration in laboratory animals and in cultured human heart cells.  LoneStar Heart is currently trying to complete the animal studies required before the Food and Drug Administration will consider permitting a human clinical trial

Lonestar Heart, however, has other products that might play a role in treating the hearts of patients whose hearts have started to enlarge. Heart enlargement results when the heart is overworked and it reacts to this overwork by enlarging. The enlargement stretches the heart and makes the walls of the heart thinner. The result is that the heart does not beat in a coordinated fashion, and patients with enlarged hearts are at risk for irregular heart beats or sudden cardiac death.

To address enlargement of the heart, LoneStar Heart has made a product called Algisyl-LVR that is a biopolymer that stiffens when it is injected into the heart. Injection of Algisyl-LVR into the walls of a heart that has enlarged thickens the heart wall without interfering with heart function. The artificial thickening of the heart walls decreases the stress on the heart and helps reverse heart enlargement. Algisyl-LVR is presently being tested in Europe in clinical trials under the product name AUGMENT-HF.  These remarkable products will hopefully be on the market before long.