Stem Cells from Muscle Can Repair Nerve Damage After Injury


Researchers from the University of Pittsburgh School of Medicine have discovered that stem cells derived from human muscle tissue can repair nerve damage and restore function in an animal model of sciatic nerve injury. These data have been recently published online in the Journal of Clinical Investigation, but more importantly, this work demonstrates the feasibility of cell therapy for certain nerve diseases, such as multiple sclerosis.

Presently there are few treatments for peripheral nerve damage. Peripheral nerve damage can leave patients with chronic pain, impaired muscle control and decreased sensation.

The senior author of this work, Henry J. Mankin, serves as the Chair in Orthopedic Surgery Research, Pitt School of Medicine, and deputy director for cellular therapy, McGowan Institute for Regenerative Medicine, and said, “This study indicates that placing adult, human muscle-derived stem cells at the site of peripheral nerve injury can help heal the lesion. The stem cells were able to make non-neuronal support cells to promote regeneration of the damaged nerve fiber.”

Muscle-derived stem cells

Workers in Mankin’s laboratory, in collaboration with Dr. Mitra Lavasani, assistant professor of orthopedic surgery, Pitt School of Medicine, grew human muscle-derived stem/progenitor cells in culture by using a culture medium suitable for nerve cells. In culture, Lavasani, Mankin and their colleagues found that when these muscle-derived stem cells were grown in the presence of specific nerve-growth factors, they differentiated into neurons and glial cells. Glial cells act as support cells from neurons. One type of glial cell that these muscle-derived stem cells could differentiate into was Schwann cells, which are the cells that form the myelin sheath around the axons of neurons to accelerate the speed at which nerve impulses are conducted.

Schwann Cell

Mankin and his colleagues then injected these human muscle-derived stem/progenitor cells into mice that had a quarter-inch injury in their right sciatic nerve. The sciatic nerve controls right leg movement. Six weeks later, the nerve had fully regenerated in stem-cell treated mice, but the untreated group showed only limited nerve regrowth and functionality. In other tests, 12 weeks after treatments, the stem cell-treated mice were able to keep their treated and untreated legs balanced at the same level while being held vertically by their tails. When the treated mice ran through a special maze, analyses of their paw prints showed that their gait, which had been abnormal, was now completely normal. Finally, treated and untreated mice experienced loss of muscle mass after nerve damage, but only the stem cell-treated mice regained normal muscle mass by 72 weeks after nerve damage.

sciatic-nerve

“Even 12 weeks after the injury, the regenerated sciatic nerve looked and behaved like a normal nerve,” Dr. Lavasani said. “This approach has great potential for not only acute nerve injury, but also conditions of chronic damage, such as diabetic neuropathy and multiple sclerosis.”

Drs. Huard and Lavasani and the team are now trying to understand how the human muscle-derived stem/progenitor cells triggered injury repair. They are also developing delivery systems, such as gels, that could hold the cells in place at larger injury sites.

The co-authors of this paper included Seth D. Thompson, Jonathan B. Pollett, Arvydas Usas, Aiping Lu, Donna B. Stolz, Katherine A. Clark, Bin Sun, and Bruno Péault, all of whom are from the University of Pittsburgh.

Human Blood Vessel-Derived Stem Cells Repair the Heart After a Heart Attack


Recently, I blogged on blood vessel-making stem cells located in the walls of blood vessels. New work on these cells from the University of Pittsburgh has shown that these CD146+ cells can also abate heart damage after a heart attack.

The ability of endothelial progenitor cells or EPCs to repair skeletal muscle is well established, but the ability of these cells to repair a damaged heart is unknown. Johnny Huard from the McGowan Institute for Regenerative Medicine at the University of Pittsburgh and his group investigated the therapeutic capabilities of human blood vessel-derived EPCs that had been isolated from skeletal muscle to treat heart disease in mice.

When mice that had been given infusions of EPCs after a heart attack were compared with mice that had received a placebo, the EPC transplanted mice definitely fared much better. Echocardiographic studies of the hearts showed that EPC transplantation reduced enlargement of the left ventricle (the main pumping chamber of the heart), and also significantly improved the ability of the heart to contract.

In addition to comparing the ability of EPCs to improve the function of the heart after a heart attack with placebos, they were also compared to stem cells known to make skeletal muscle. These stem cells are called “CD56+ myogenic progenitor cells,” which is a mouthful. CD56+ myogenic progenitor cells or CD56+ MPCs can form skeletal muscle; and infusions of them can improve the structure of the heart after a heart attack and prevent it from deteriorating. However, transplanted EPCs were superior to CD56+ MPCs in their ability to heal the heart after a heart attack.

The transplanted EPCs were able to substantially reduced scarring in the heart, and significantly reduced inflammation in the heart. In fact, then the culture medium in which EPCs were grown was injected into mouse hearts after a heart attack, this medium also suppressed inflammation in the heart.

When Huard and his co-workers examined the genes made in the EPCs, they found that these stem cells cranked out proteins known to decrease inflammation (IL-6, LIF, COX-2 and HMOX-1 for those who are interested), especially when the cells were grown under low oxygen conditions. This is significant because in the heart after a heart attack, blood vessels have died off and the supply of blood to the heart is compromised. The fact that these cells are able to do this under these harsh conditions shows that they make exactly the most desirable molecules under these conditions.

The biggest boon for these cells came from examinations of blood vessel formation in the heart. Blood vessel production in the EPC-transplanted hearts was significantly increased. The EPCs formed a host of new blood vessels and extending “microvascular structures” or smaller supporting blood vessels and larger capillary networks too.

Once again, when grown under oxygen poor conditions, the EPCs jacked up their expression of pro-blood vessel-making molecules (VEGF-A, PDGF-β, TGF-β1 and their receptors). When EPCs were labeled with a green-glowing protein, fluorescence tracking showed that they actually fused with heart cells, although it must be emphasized that this was a minor event.

These pre-clinical studies show remarkable improvements in the heart after a heart attack, and they apparently induce these improvements through several different mechanisms. They make new structures and they secrete useful molecules. These significantly successful results should provide the basis for clinical trials with these cells.