Development of Innovative Treatment with Designer Cells Modified from Adipose-Derived Stem Cells
Among neurological diseases, ischemic stroke is one of the most common neurological diseases and is a major cause of long-term care needs. Previous studies have shown that controlling inflammation and promoting neurite outgrowth after ischemic stroke are necessary to improve post-stroke prognosis, and various therapies such as drugs and mesenchymal stem cell transplantation have been tried with limited efficacy. Recent reports have shown that individual differences in response to mesenchymal stem cell transplantation are large. Also, they showed that the quantity and quality of extracellular vesicles in the blood after transplantation are important for its efficacy. Interestingly, the amount of trophic factors such as hepatocyte growth factor (HGF) and miRNAs promoting nerve regeneration are lower in mesenchymal stem cells from elderly patients than in younger patients. Increased expression of miRNAs associated with inflammation and aging has also been reported in elderly patients. Therefore, it is important to develop mesenchymal stem cells with additional functions needed for therapy in diseases such as ischemic stroke, a disease in which many elderly people suffer from.
We have been studying HGF and R-spondin (RSPO). Specifically, we have found that overexpression of HGF in the brain after ischemic stroke by gene transfer improves cognitive dysfunction in the chronic phase of cerebral infarction by improving neurite outgrowth and microcirculation [1]. We have also found that RSPO, a facilitator of Wnt/β-catenin signaling, is a novel molecule that improves paralysis in the chronic phase of stroke by suppressing TLR inflammation and promoting neurite outgrowth [2].
Based on this background, our laboratory is trying to create new adipose-derived stem cells transfected with molecules such as HGF, RSPO, and genes that promote their accumulation at the site of injury. Our final goal is to clarify the therapeutic effects of these cells in ischemic stroke, spinal cord injury, and autoimmune diseases.
Exploration of Novel Inflammation Regulation/Neuroregeneration Molecules and Their Application to Treatment of Ischemic Stroke and Incurable Diseases
We have been searching for novel molecules involved in the regulation of inflammation and neurite outgrowth because of the limitation of conventional ischemic stroke therapies that target existing molecules. One of them is the aforementioned RSPO, and we found RANKL/RANK signaling, which is expressed in activated microglia after cerebral infarction and regulates inflammation by TLRs .
Furthermore, we found that a partial peptide of RANKL binding site to RANK, excluding the site involved in osteoclastic progenitor cell differentiation, strongly suppressed TLR signaling-related inflammation in microglia and Mφ. We found it to be a potential therapeutic agent in the acute phase of stroke [4, 5]. The peptide has also shown therapeutic effects in sepsis, psoriasis, and pulmonary fibrosis related to TLR inflammation [6, 7]. We are currently collaborating with the University of Tokushima to make the peptide more effective.
We have also newly found that RSPO, a facilitator of Wnt/β-catenin signaling, which is important for the expression of mesenchymal stem cell effects, improves paralysis in the chronic phase of stroke by suppressing TLR inflammation and neurite outgrowth [5].
In addition to these discoveries, we will continue to search for promising novel molecules for the treatment of ischemic stroke from a multifaceted perspective.
References
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- Nan J, et al. Immunohorizons. 438-447, 2021.
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- Nan J, et al. Sci Rep. 12474, 2022.