Stem Cells that Promote Nerve Regeneration


A study by Johns Hopkins researchers W. P. Andrew Lee and Gerald Brandacher have used stem cells from fat to promote nerve regeneration in rats that have suffered paralyzing leg injuries and in other rodents that have received hind-leg transplants.

These findings have shown that mesenchymal stem cells (MSCs) can stimulate nerve regeneration, and deepen our understanding of how MSCs improve nerve regeneration after injury and limb transplant, while potentially minimizing the need for lifelong immunosuppression after reconstructive surgery to replace a lost limb.

Medical student John Pang said, “Mesenchymal stem cells may be a promising add-on therapy to help damaged nerves regenerate. We obviously need to learn much more, but we are encouraged by what we learned from these experiments.”

MSCs have the ability to readily differentiate into bone, cartilage, and fat cells, but in the laboratory, scientists have been able to extend the possible cell fates that MSCs can form, including nerve and blood vessel cells.

Another advantage of MSCs is their ability to escape recognition by the immune system. MSCs secrete a variety of molecules that suppress the immune response against them. According to Pang it is this very property of MSCs that researchers hope to use in order to regenerate nerves without requiring patients to take immunosuppressive drugs.

Harvesting MSCs from fat is relatively easy, but they can also be isolated from bone marrow. Although, bone marrow aspirations can cause more pain in some pain than liposuction.

In this experiment, researchers used three different groups of rodents. In one group, the rats had their femoral nerves cut and repaired. In the second group, the rats received a hind-leg transplant, and in the third group, the rats received a different type of transplant. Some of these rats had MSCs directly injected into the sciatic nerve, and others had the MSCs intravenously administered. After 16 weeks, the researchers say the rats with severed and repaired nerves with MSCs showed significant improvements in nerve regrowth and nerve function. Those with transplants from similar rats appeared to also show benefits.

Sciatic nerve

Those rats who transplants came from dissimilar rodent types – a situation similar to those patients who receive transplants from cadavers – rejected their new limbs.  Thus MSCs might be a adjuvant treatment for patients with nerve damage.

Stem Cells Improve Cognition After Brain Injury


Research led by Charles Cox at the University of Texas Health Science Center has shown that stem cell therapy given during the critical time window after traumatic brain injury promotes lasting cognitive improvement. These experiments, which were published in the latest issue of the journal Stem Cells Translational Medicine, provide a pre-clinical model for experiments with larger animals.

After the brain has suffered a traumatic injury, there are few treatment options. Damage to the brain can be severe, and can also cause ongoing neurological impairment. Approximately half of all patients with severe head injuries need surgery to remove or repair ruptured blood vessels or bruised brain tissue.

In this work from Cox’s lab, stem cells from bone marrow known as multipotent adult progenitor cells (MAPCs) were used. MAPCs seem to be a subpopulation of mesenchymal stem cells, and they have a documented ability to reduce inflammation in mice immediately after traumatic brain injury. Unfortunately, no one has measured the ability of MAPCs to improve the condition of the brain over time.

Cox, Distinguished Professor of Pediatric Surgery at the UTHealth Medical School and in collaboration with the Children’s Fund, Inc., injected two groups of brain-injured mice with MAPCs two hours after injury and then once again 24 hours later. One group received a dose of 2 million cells per kilogram and the other a dose five times greater.

After four months, those mice that had received the stronger dose not only continued to have less inflammation, but they also showed significant gains in cognitive function. Laboratory examination of the brains of these rodents confirmed that those that had received the higher dose of MAPCs had better brain function than those that had received the lower dose.

According to Cox, “Based on our data, we saw improved spatial learning, improved motor deficits and fewer active antibodies in the mice that were given the stronger concentration of MAPCs.” Cox also indicated that this study indicates that intravenous injection of MAPCs might very well become a viable treatment for people with traumatic brain injury in the future.

Cox, who directs the Pediatric Surgical Translational Laboratories and Pediatric Program in Regenerative Medicine at UTHealth, is a leader in the field of autologous and blood cord stem cells for traumatic brain injury in children and adults. Results from a phase 1 study were published in a March 2011 issue of Neurosurgery, the journal of the Congress of Neurological Surgeons. Cox also directs the Pediatric Trauma Program at Children’s Memorial Hermann Hospital.

Benefits of stem cells in treating MS declines with donor’s age


MS is a neurodegenerative disease characterized by inflammation and scar-like lesions throughout the central nervous system (CNS). There is no cure and no treatment eases the severe forms of MS. But previous studies on animals have shown that transplantation of mesenchymal stem cells (MSCs) holds promise as a therapy for all forms of MS (see Bai L, et al., Glia 2009 Aug 15;57(11):1192-203). The MSCs migrate to areas of damage, release trophic (cell growth) factors and exert protective effects on nerves and regulatory effects to inhibit T cell proliferation.

Several clinical trials examining the ability of fat-derived MSCs to treat MS patients have been conducted. Unfortunately, most of these studies are rather small and the results are all over the place. One study treated ten patients with MSCs injected intrathecally (just under the meninges that cover the brain and spinal cord) and the results were mixed; 6/10 improved, 3 stayed the same and one deteriorated. Another study treated ten patients with intravenous fat-derived MSCs and the patients showed symptomatic improvement, but when MRIs of the brain were examined, no improvements could be documented. A third study treated 15 people with intrathecal injections and IV administrations of MSCs, and some stabilized. A fourth study only examined 3 patients treated with a mixture of their own fat-derived MSCs and fat-derived MSCs from another person. In all three cases, their MRIs and symptoms improved. A fifth study used umbilical cord MSCs administered intravenously and the patient showed substantial improvement (for review see Tyndall, Pediatric Research 71(4):433-438).

These results are somewhat encouraging, but also somewhat underwhelming and clinical trials go. Why did some work and other not work as well? In order to understand why, researchers must understand the biologic changes and therapeutic effects of older donor stem cells. A new study appearing in the journal STEM CELLS Translational Medicine is the first to demonstrate that adipose-derived MSCs donated by older people are less effective than cells from their younger counterparts.

Fortunately, all the available MS-related clinical trials have confirmed the safety of autologous MSC therapy. As to the efficacy of these cells, however, it is unclear if MSCs derived from older donors have the same therapeutic potential as those from younger ones.

“Aging is known to have a negative impact on the regenerative capacity of most tissues, and human MSCs are susceptible to biologic aging including changes in differentiation potential, proliferation ability and gene expression. These age-related differences may affect the ability of older donor cells to migrate extensively, provide trophic support, persist long-term and promote repair mechanisms,” said Bruce Bunnell, Ph.D., of Tulane University’s Center for Stem Cell Research and Regenerative Medicine. He served as lead author of the study, conducted by a team composed of his colleagues at Tulane.

In their study, Bunnell and his colleagues induced an MS-like disease in laboratory mice called chronic experimental autoimmune encephalomyelitis (EAE). Then they treated them before disease onset with human adipose-derived MSCs derived from younger (less than 35 years) or older (over age 60) donors. The results corroborated previous studies that suggested that older donors are less effective than their younger counterparts.

“We found that, in vitro, the stem cells from the older donors failed to ameliorate the neurodegeneration associated with EAE. Mice treated with older donor cells had increased inflammation of the central nervous system, demyelination leading to an impairment in movement, cognition and other functions dependent on nerves, and a proliferation of splenocytes [white blood cells in the spleen], compared to the mice receiving cells from younger donors,” Dr. Bunnell noted.

In fact, the proliferation of T cells (immune cells that attack the myelin sheath in MS patients) in these mice indicated that older MSCs might actually stimulate the proliferation of the T cells, while younger stem cells inhibit T cell proliferation. T cells are a type of white blood cell in the body’s immune system that help fight off disease and harmful substances. When they attack our own tissues, they can cause diseases like MS.

As such, Dr. Bunnell said, “A decrease in T cell proliferation would result in a decreased number of T cells available to attack the CNS in the mice, which directly supports the results showing that the CNS damage and inflammation is less severe in the young MSC-treated mice than in the old MSC-treated mice.”

“This study in an animal model of MS is the first to demonstrate that fat-derived stem cells from older human donors have less therapeutic effectiveness than cells from young donors,” said Anthony Atala, M.D., editor of STEM CELLS Translational Medicine and director of the Wake Forest Institute for Regenerative Medicine. “The results point to a potential need to evaluate cell therapy protocols for late-onset multiple sclerosis patients.”