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Aim for treatment of neurological diseases with adipose-derived stem cells added inflammatory control/neuroregenerative functions

Among neurological diseases, ischemic stroke affects a number of patients and requires nursing care. Because the therapeutic effects of existing treatments are limited, the development of a novel treatment is desired. Previous studies have revealed that it is necessary to control post-stroke inflammation and promote neurite elongation in order to improve the prognosis of ischemic stroke. Various treatment methods have been attempted, including drug therapy and mesenchymal stem cell (MSC) transplantation; however, their effects were limited. We believe that novel anti-inflammatory and regenerative peptides and MSC transfected with genes encoding novel molecules involved in the regulation of inflammation and neurite outgrowth will be a promising strategy to treat ischemic stroke.

For such molecules, we have been studying hepatocellular growth factor (HGF), partial peptide of RANKL, R-spondin (RSPO). Specifically, we have found that overexpression of HGF in the brain by gene transfer after ischemic stroke leads to neuritogenesis and microcirculation improvement, by which the cognitive dysfunction in the chronic phase of ischemic stroke is improved [1]. We have also found that the partial peptide of RANKL controls Toll-like receptor (TLR) signaling in microglia that is the origin of post-ischemic inflammation and controls the worsening of acute ischemic stroke [2-4]. Another finding is that RSPO, that potentiates Wnt/β-catenin signaling, improves paralysis in the chronic phase of ischemic stroke by inhibiting TLR-driven inflammation and promoting neurite outgrowth [5].

On the other hand, MSC transplantation is expected to be a new treatment option for ischemic stroke but has not been reported to show effects that satisfy the primary endpoint. Recently, it has been reported that the treatment response varies between individuals, that reflects the amount of extracellular vesicles in blood after transplantation. Also, in aged MSCs, nutritional factors such as HGF and the amount of miRNAs that promote neuroregeneration are decreased, whereas the expression of miRNAs related to inflammation and aging is increased compared to younger MSCs. Because many stroke patients are elderly, it is considered necessary to develop rejuvenated MSCs with additional functions.

Based on the above background, our laboratory is trying to develop adipose-derived stem cells transfected genes encoding such as HGF and RSPO, and molecules, which promote the accumulation of MSCs in the damaged area. Our final goal is to apply them as a new treatment for ischemic stroke, spinal cord injury, multiple sclerosis, and other disorders.

<References / Conference presentation>
1. Shimamura M, et al. Hypertension. 47, 742-51, 2006.
2. Shimamura M, et al. PNAS. 111, 8191-6, 2014.
3. Kurinami H, et al. Sci Rep. 6, 38062, 2016.
4. Shimamura M, et al. Sci Rep. 8, 17770, 2018.
5. Shimamura M, et al. The 65th Annual Meeting of the Japanese Society of Cerebral Blood Flow and Metabolism.