Combination of Mesenchymal Stem Cells and Schwann Cells Used to Treat Spinal Cord Injury

Spinal cord injuries represent an immensely difficult problem for regenerative medicine. The extensive nature of the damage to the spinal cord is difficult to repair, and the transformation that the injury wrecks in the spinal cord makes the spinal cord inhospitable to cellular repair.

Fortunately some headway is being made, and several clinical trials have shown some success with particular stem cells. Neural stem cells can differentiate into new neurons and glial cells and replace dead or damaged cells (see Tsukamoto A., et Al., Stem Cell Res Ther 4,102, 2013 ). Oligodendrocyte progenitor cells (OPCs) derived from embryonic stem cells or other sources can replace the myelin sheath that died off as a result of the injury (Alsanie WF, Niclis JC, Petratos S. Stem Cells Dev. 2013 Sep 15;22(18):2459-76).  Olfactory ensheathing cells can move across the glial scar and facilitate the regrowth of severed axons across the scar (Tabakow P, et al., Cell Transplant. 2014;23(12):1631-55). Mesenchymal stem cells can mitigate the inflammation in the damaged spinal cord, and, maybe, stimulate endogenous stem cell populations to repair the spinal cord (Geffner L.F., et al., Cell Transplant 17,1277, 2008). Therefore, several cell types seem to have some ability to heal the damaged spinal cord.

A new clinical trial from the Zali laboratory at Shahid Beheshti University of Medical Sciences, in Tehran, Iran, has examined the used of two different stem cells to treat spinal cord injury patients. This trial was a small, Phase I trial that only tested the safety of these treatments.

Zali and his colleagues assessed the safety and feasibility of transplanting a combination of bone marrow mesenchymal stem cells (MSCs) and Schwann cells (SCs) into the cerebral spinal fluid (CSF) of patients with chronic spinal cord injury. SCs are cells that insulate peripheral nerves with a myelin sheath. Even though SCs are not found in the central nervous system, they do the same job as oligodendrocytes, and several experiments have shown that when transplanted into the central nervous system, SCs can do the job of oligodendrocytes in the central nervous system.

In this trial, six subjects with complete spinal cord injury according to International Standard of Neurological Classification for Spinal Cord Injury (ISNCSCI) developed by the American Spinal Injury Association were treated with co-transplantation of their own MSCs and SCs by means of a lumbar puncture. The neurological status of these patients was ascertained by the ISNCSCI and by assessment of each patient’s functional status according to the Spinal Cord Independent Measure. Before and after cell transplantation, the spinal cord of each patient was imaged by means of magnetic resonance imaging (MRI). All patients also underwent electromyography, urodynamic study (UDS) and MRI tractograghy before the procedure and after the procedure if patients reported any changes in motor function or any changes in urinary sensation.

In a span of 30 months following the procedure, radiological findings were unchanged for each patients. There were no signs or indications of neoplastic tissue overgrowth in any patient. In one patients, their American Spinal Injury Association class was downgraded from A to B. This same patients had increased bladder compliance, which correlated quite well with the axonal regeneration detected in MRI tractography. None of these patients showed any improvement in motor function.

To summarize, there were no adverse effects detected around 30 months after the transplantations. These results suggest that this stem cell combination is safe as a treatment for spinal cord injury. While improvement of observed in one patients, because the trial was not designed to investigate the efficacy of the treatment, it is difficult to make any hard-and-fast conclusions about the efficacy of this treatment at this time. However, the fact that one patient did improve is at least encouraging.

These data were reported in the journal Spinal Cord (Spinal Cord. 2015 Nov 3. doi: 10.1038/sc.2015.142).

Skin Cells Converted into Placenta-Generating Cells

Researchers from the laboratory of Yosef (Yossi) Buganim at Hebrew University of Jerusalem have used genetic engineering techniques to directly reprogram mouse skin cells into stable, and fully functional placenta-generating cells called induced trophoblast stem cells (iTSCs).

The placenta forms a vital link between a mother and her baby. When the placenta does not work as well as it should, the baby will receive less oxygen and nutrients from the mother. Consequently, the baby might show signs of fetal stress (that is the baby’s heart does not work properly), not grow nearly as well, and have a more difficult time during labor. Such a condition is called “placental insufficiency” and it can cause recurrent miscarriages, low birth weight, and birth defects.

Placental dysfunction has also been linked to a condition called fetal growth restriction (AKA Intrauterine growth restriction). Intrauterine growth restriction or IUGR is a condition characterized by poor growth of a baby while in the mother’s womb during pregnancy.

How can scientists study the placenta? Virtually all attempts to grow placental cells in culture have been largely unsuccessful.

Buganim and his colleagues have solved this problem. A screen for genes that support the development of the placenta yielded three genes: GATA3, Eomes, and Tfap2c. Next the Buganim team took mouse skin fibroblasts and forced the expression of these three placenta-specific genes in them. This initiated a cascade of events in the cells that converted them into stable and fully functional placenta-generating cells.

These skin-derived TSCs behave and look like native TSCs and they also function and contribute to developing placenta. The Bugamin laboratory used mouse cells for these experiments, but they want to expand their experiments to include human cells to make human iTSCs.

The success of this study could potentially give women who suffer from recurrent miscarriage and placental dysfunction diseases the ability to have healthy babies. The embryo is not at risk from such cells, since iTSCs integrate into the placenta and not into the embryos itself.

See Cell Stem Cell. 2015 Sep 22. pii: S1934-5909(15)00361-6. doi: 10.1016/j.stem.2015.08.006.

Cardiac Muscle Cells Work as Well as Cardiac Progenitor Cells to Repair the Heart

Cell therapies for the heart after a heart attack provide some healing, but the success of these treatments in inconsistent and the majority of the improvements are modest. Whole bone marrow or even bone marrow stem cells can promote the growth of new blood vessels in the heart after a heart attack (Zhou Y, et al., Ann Thorac Surg. 2011 Apr;91(4):1206-12). The treatment of the heart after a heart attack, can also stimulate the regeneration of new heart muscle, but such new muscle comes from endogenous stem cells populations that are induced by the implanted stem cells (Hatzistergos KE, et al., Circ Res. 2010 Oct 1;107(7):913-22).

Nevertheless, the clinical trials with bone marrow cells have produced mixed results. Bone marrow implants work well in some patients and hardly at all in others. The quality of the patient’s bone marrow might be part of the reason for the disparate findings of these trials, but the fact remains, that using cells that can replace dead heart muscle can potentially treat a damaged heart better than bone marrow stem cells.

Pluripotent stem cells, either embryonic stem cells or induced pluripotent stem cells (iPSCs) can efficiently differentiate into heart muscle cells, but a debate remains as to which cell does a better job for healing the heart: Should young heart muscle cells called progenitor cells be used, or can mature heart muscle cells do the job just as well?

Charles Murray from the University of Washington, who has pioneered the use of stem cells to treat the hearts of laboratory animals, and his colleagues tested the ability of heart progenitor cells to repair the heart versus mature heart muscle cells. Both of these cell types were tested against bone marrow stem cells as a control.

Murray and his colleagues used heart muscle cells made from human embryonic stem cells and heart progenitor cells made from the same human embryonic stem cell line to treat the hearts of laboratory rats. These rats were given heart attacks and then the cells were injected directly into the walls of the heart. Injections were given four days after the heart attacks were induced. Each treatment group contained ten rats, including a control group that received injections of cells that are known to possess no healing capabilities.

Measurements of heart function four weeks after treatment showed that both heart progenitor cells and mature heart muscle cells improved the heart equally well and both cells improved heart significantly better than bone marrow stem cells.

Murray said, “There’s no reason to go back to more primitive cells, because they don’t seem to have a practical advantage over more definitive cells types in which the risk for tumor formation is lower.”

In the future, Murry would like to determine if these same cells work in a larger animal model system and then, eventually start clinical trials in human heart attack patients.

Fernandes and Chong et al., Stem Cell Reports, October 2015 DOI: 10.1016/jstemcr.2015.09.011.