Radiation-induced brain injury
Brain radiation is a widely used tool to help control brain tumor growth, but leads to significant cognitive deficits, especially in patients who undergo long-term whole-brain radiation. The molecular mechanisms of the cognitive impairment caused by radiation are poorly understood, but prolonged activation of the immune cells of the brain (microglia) has been implicated.
Dr. Burns and colleagues defined the transcriptome of acute and chronic irradiation in microglia and identified chronic changes that were highly reminiscent of changes occurring in natural aging. These results suggest that aging-related changes may be accelerated by irradiation and provide a starting point for understanding the microglial signature of aging-related and radiation-related cognitive decline. Subsequent unpublished work reveals profound enrichment of the microglial signature in human neurodegeneration and a correlation with poor survival rates in patients with glioblastoma.
Given the significant overlap between aging and radiation signatures, research in the Mayo Clinic Regenerative Neurosurgery and Neuro-Oncology Lab is working to harness promising anti-aging strategies, such as heterochronic parabiosis, to discriminate between the beneficial and pathological effects of microglial activation, enabling focused strategies to promote rejuvenation. Additionally, Dr. Burns' lab is actively exploring the use of certain progenitor cells, which also shows promise for repairing radiation-induced brain injury.
Translation of regenerative neurological therapies
Common themes of inflammation, oxidative stress, mitochondrial dysfunction and protein mishandling recur across multiple neurological diseases. To date, therapeutic strategies targeting unique features of individual diseases studied in animal models have proved unsuccessful in clinical trials.
To identify recurrent themes across human neurological diseases, Dr. Burns and colleagues took an alternate approach, performing a rigorous transcriptional meta-analysis of available human data for Alzheimer's disease, Huntington's disease, Parkinson's disease and amyotrophic lateral sclerosis, thereby defining the conserved transcriptional signature of human neurodegeneration.
Comparison of this human signature to that of neurodegenerative animal models revealed striking differences. These data help explain why therapies that appear promising in animal models of neurodegeneration have rarely succeeded in human clinical trials. This work helps provide a path forward in developing innovative translational pipelines that yield therapies that work in humans rather than mice.
Rigorous science in regenerative medicine
When the field of neural cell transplantation was really taking off, thymidine analogs such as 5-bromodeoxyuridine (BrdU) became the standard and accepted tools for labeling and identifying grafted cells after transplantation. However, Dr. Burns and colleagues demonstrated that these labels may be released from cells that die after transplantation and may become incorporated into local dividing host cells, which could then masquerade as transplanted cells.
This revelation cast doubts upon a substantial body of prior literature claiming plasticity of adult somatic stem cells and helped pave the way toward more reproducible findings in the previously controversial field of adult stem cell plasticity. Maintaining the highest level of scientific rigor ensures that regenerative work at Mayo Clinic not only leads the field in discovery and innovation but also provides a solid foundation for the development of effective human therapies.
Germ cell tumors from adult bone marrow
While evaluating stem cell-based therapies in rodent stroke models, Dr. Burns and colleagues noticed that certain bone marrow-derived cell lines formed tumors after transplantation.
Further evaluation revealed embryonic yolk sac tumors in grafts derived from multipotent adult progenitor cells (MAPCs) expressing high levels of the transcription factor Oct4. MAPCs reproducibly resulted from spontaneous in vitro epigenetic reprograming of CD45-bone marrow stem cells to an embryonic hypoblast-like state with marked demethylation of the Oct4 promoter.
Interestingly, systemic delivery of the same cells in other mouse models yielded therapeutic effects without tumor formation, including restoring immune function in immune deficient mice. As such, these results caution that cells that appear safe in one setting could still misbehave in other settings, especially when cells are implanted at high density into a confined space. The Regenerative Neurosurgery and Neuro-Oncology Lab and colleagues continue driving efforts to establish standardized strategies that ensure the safety of adult-derived cells used for regenerative therapies.