Mice with MS-like Disease Unexpectedly Walk After Stem Cell Transplantation
Researchers at the University of California stumbled upon an unexpected outcome while studying the common problem of stem cell rejection following transplantation. Scientists injected human neural precursor cells (hNPCs) derived from human embryonic stem cells (hESCs) into the spinal cords of mice infected with the neurotropic JHM strain of mouse hepatitis virus (JMHV). Persistent infection with this particular virus causes an MS-like condition in mice characterized by demyelination, neuroinflammation, and hind-limb paralysis.
As expected, the stem cells injected into the JHMV-infected mice were completely rejected by the immune system within 8 days. However, unexpectedly, the hNPC-transplanted mice experienced improved motor skills and a reduction in neuroinflammation and demyelination about two weeks after the injections. Results of a follow-up study cofunded by the National MS Society and the California Institute for Regenerative Medicine are published in the journal Stem Cell Reports in the article, “Human Neural Precursor Cells Promote Neurologic Recovery in a Viral Model of Multiple Sclerosis.”
Tom Lane, a University of California, Irvine pathologist who now works at the University of Utah recalls receiving a call from his postdoctoral fellow, Lu Chen, who said, “These mice are walking.” Lane tells The Salt Lake Tribune that he had doubts, but went to the lab to see for himself. "Sure enough, there were groups of mice that had gone from being paralyzed to walking around the cage," Lane said.
In the current study, researchers at the Center for Regenerative Medicine at The Scripps Research Institute sought to evaluate the effects of hNPCs in promoting clinical recovery in mice with the JHMV-induced model of demyelinating disease similar to multiple sclerosis. The findings could potentially direct future research and contribute to discovering new methods of treating MS, a disease which affects more than 2.3 million people worldwide according to updated statistics presented by the Multiple Sclerosis International Federation.
Current treatments for MS include disease-modifying therapies (DMTs) that reduce disease activity and symptomatic treatments that assist patients in living better lives. There are no treatments to repair the damage caused by MS. However, pre-clinical and clinical research into neural repair and regeneration are on-going. Last summer, the FDA approved a unique stem cell trial being conducted at the Tisch MS Research Center of New York in which 20 patients will receive three intrathecal (into the cerebrospinal fluid) injections of neural progenitor cells (NPCs) derived from their own bone marrow.
Scientists at The Scripps Research Institute injected 96 mice into the spine with human embryonic stem cells in immunocompetent mice (with fully functioning immune systems) who had virally-induced MS. The presence of the injected stem cells diminished over days 0-8 post-transplantation, but during that short time period they apparently triggered certain cells in the immune system to reduce inflammation, decrease demyelination, and enhance remyelination over a longer, sustained period of time.
Within ten to 14 days, symptoms were partially reversed in 66 (73%) of the mice injected with hESC-derived hNPCs, but only 9 of the 63 mice (14%) transplanted with the control (human fibroblasts) improved. Improvements persisted for up to 6 months post-transplantation. The use of living cells and intraspinal injection were necessary for clinical recovery as researchers found that transplantation with dead cells or delivery of cells via intravenous or intraperitoneal injection did not result in improved clinical outcome.
The reduced neuroinflammation seen here correlated with an increased number of CD4+CD25+FOXP3+ regulatory T cells (Tregs) within the spinal cords, suggesting that the transplanted hNPCs may have promoted recovery through Treg-mediated mechanisms. When hNPC-transplanted mice were treated with an anti-CD25 monoclonal antibody, which efficiently blocks Treg activity, functional improvement was inhibited and neuroinflammation increased. When hNPCs were cocultured with activated T cells, the proliferation of T cells was reduced and Treg numbers were increased. Researchers also discovered that hNPCs increased Treg frequency, in part, through the secretion of TGF-β1 and TGF-β2 (transforming growth factor-β) which are known to have neuroprotective qualities.
It is interesting that human embryonic neural precursor cells which were cultured in a unique way and injected directly into the spine of mice with virally-induced MS-like disease experienced sustained clinical improvements over time. However, we must keep in mind that this research is very far removed from actual testing in humans which may ultimately lead to the development of new treatments. Tom Lane says that he wants to test the therapy in another mouse model available at the University of Utah, where he recently took a faculty position, hoping to take advantage of the university’s system for translating research into treatments.
Chen L, Coleman R, Leang R, et al. Human Neural Precursor Cells Promote Neurologic Recovery in a Viral Model of Multiple Sclerosis. Stem Cell Reports. 2014. doi:10.1016/j.stemcr.2014.04.005. Epub 2014 May 15.
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