Development of Innovative Treatment with Designer Cells Modified from Adipose-Derived Stem Cells
Ischemic Stroke, which affects a large number of patients and is a leading cause of the need for long-term care, faces limitations with existing treatments, creating a strong need for the development of new therapeutic strategies. Previous research has shown that appropriate control of inflammation and the promotion of neurite outgrowth are crucial for improving prognosis following cerebral infarction; however, the efficacy of treatments attempted to date, such as drug therapy and mesenchymal stem cell transplantation, has been limited. Furthermore, recent reports have shown that there is significant individual variability in treatment response to mesenchymal stem cell transplantation (Neurology 2021), and it has become clear that there is also marked individual variation in the cytokine secretion capacity of adipose-derived stem cells (ADSCs) (Stem Cell Res Ther 2023).
Through a collaborative study with AS Medical Support Co., Ltd., we found that, among the cytokines secreted by human-derived ADSCs, there is particularly significant individual variation in the expression of hepatocyte growth factor (HGF) (Figure 1). Furthermore, we have demonstrated that ADSCs with low HGF expression exhibit limited efficacy in improving paralysis in a mouse cerebral infarction model (Figure 2, Manuscript submitted). A similar trend has been observed in autoimmune disease models, suggesting that differences in HGF expression may be deeply involved in treatment responsiveness.
Based on these results, we believe that we can design more functional ADSCs by enhancing HGF expression to maximize the inherent therapeutic potential of ADSCs and by incorporating other genes that enhance their ability to efficiently migrate to the site of the lesion (Figure 3). Currently, our laboratory is working on the development of more effective genetically modified ADSCs for cerebral infarction and autoimmune diseases based on this concept.
Exploration of Novel Inflammation Regulation/Neuroregeneration Molecules and Their Application to Treatment of Ischemic Stroke and Incurable Diseases
Recognizing the limitations of existing ischemic stroke treatments that target established molecules, we have been searching for novel molecules involved in inflammation control and neurite outgrowth. Among these, we identified RSPO, mentioned earlier, and the RANKL/RANK signaling pathway, which is expressed in activated microglia following cerebral infarction and regulates TLR-mediated inflammation.
Furthermore, we discovered that a partial peptide derived from the RANKL-RANK binding site—excluding the region involved in osteoclast precursor cell differentiation—potently suppresses TLR-mediated inflammation in microglia and macrophages, revealing its potential as a therapeutic agent for the acute phase of cerebral infarction [1–3]. This peptide has also demonstrated therapeutic effects in sepsis, psoriasis, and pulmonary fibrosis, which are associated with TLR-mediated inflammation [4-6], and we are currently confirming its efficacy in osteoarthritis and osteoporosis models through collaborative research with the Department of Orthopedics [7,8].
We have also discovered R-spondin3 [9] and fibroblast activation protein (FAP) as novel molecules that control inflammation following cerebral infarction. FAP is a member of the DPP family and has been studied as a key molecule involved in immune tolerance within the tumor microenvironment and fibrosis in heart disease. Epidemiologically, it has been reported that low levels of FAP in the blood are associated with worsening cerebral infarction and poor prognosis; however, it remained unclear whether FAP was a friend or foe in the treatment of cerebral infarction. We have discovered that FAP is a key molecule that suppresses inflammation and protects neurons in cerebral infarction (Figure 4), and that it acts as an “ally” in cerebral infarction treatment, potentially serving as a new therapeutic target [10, manuscript submitted].
Beyond these discoveries, we intend to continue our efforts to identify promising new molecules for the treatment of cerebral infarction from a multifaceted perspective.
The Challenge of Developing New Cancer Treatments Through the Elucidation of Tumor Immune Mechanisms
Cancer utilizes various cells to evade the immune system, creating a favorable environment known as the tumor microenvironment (TME). In the TME, factors promoting tumor growth are produced, and antitumor immunity is suppressed, leading to the progression of cancer. In recent years, various cancer immunotherapies have been developed, but their therapeutic efficacy is influenced by the tumor microenvironment. Therefore, to achieve favorable treatment outcomes, it is necessary to overcome the immunosuppressive nature of the tumor microenvironment.
Through our research on the tumor microenvironment, we are exploring new possibilities for cancer treatment. Specifically, we use immunostimulants and molecular drugs to stimulate the TME, thereby overcoming the suppression of antitumor immunity to enhance it and overcome resistance to PD-1 antibody therapy (Figure 5). Furthermore, we are improving the formulation process for whole-cell cancer vaccines to develop next-generation cancer vaccines capable of efficiently breaking immune tolerance and inducing antitumor immune responses, with the aim of preventing cancer metastasis and recurrence (Figure 6). This research is led by CHANG Chin-Yang.
References
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- Shimamura M, et al. 5: Stroke 2023.
- 島村宗尚 他. 第51回日本脳卒中学会、2026年、口演