Institute of Biomedical Research and InnovationDepartment of Regenerative Medicine Research

Research focus

(1) Establishment of optimized stem cell therapy for stroke
Our Achievements

(a) Stem cell transplantation improves neurogenesis in murine stroke model
We have established a highly reproducible stroke mouse model which is ideal for the evaluation of various cell therapies. Using this model, we have found that hematopoietic stem cell transplantation after stroke enhances cerebral angiogenesis and the angiogenesis is essential for endogenous neurogenesis after stroke (Taguchi et al. J. Clin. Invest. 2004) (Fig. 2).
(b) Stem cell transplantation improves neurological recovery in patients with stroke
We conducted a clinical trial of autologous hematopoietic stem cell transplantation for patients with severe stroke. We have found that stem cell transplantation improves functional recovery with increased cerebral metabolism (Taguchi et al. Stem Cells Dev. 2015) (Fig. 3).
(c) Identification of the mechanism of action of stem cell therapy
We have revealed that the mechanism of action of hematopoietic stem cells is direct cell-cell interaction via gap junctions (Fig. 4) (Kikuchi-Taura et al. Stroke 2020). Furthermore, we have revealed that mechanism of action of mesenchymal stem cells is also direct cell-cell interaction via gap junctions (Fig. 5) (Kikuchi-Taura et al. StemCells 2021).

(Description of Fig. 2)

Fig. 2 Therapeutic angiogenesis for endogenous neurogenesis

(A) Endogenous neurogenesis is activated after stroke, but stroke induced neuronal stem cells can’t survive because of unfavorable environments. (B) Hematopoietic stem cell transplantation induces angiogenesis and newly formed vessels support survival and maturation of stroke induced neuronal stem cells followed by neurological recovery. (Quoted/modified from J. Clin. Invest. 2004).

(Description of Fig. 3)

Fig. 3 Improvement of cerebral metabolism and neurological function by autologous hematopoietic stem cell transplantation in stroke patients

(A) Increased cerebral metabolic rate of oxygen (CMRO2) was observed both at ipsilateral and contralateral side by hematopoietic stem cell transplantation. (B) Improvement of NIHSS（National Institutes of Health Stroke Scale）scores was observed by autologous cell transplantation (Quoted/modified from Stem Cells Dev. 2015).

(Description of Fig. 4)

Fig. 4 Mechanism of action of hematopoietic stem cell therapy

Hematopoietic stem cell provides energy source, such as glucose, to injured cell through gap junction that turns on activation switch (Quoted/modified from Stroke 2020).

(Description of Fig. 5)

Fig. 5 Mechanism of action of mesenchymal stem cell therapy

Mesenchymal stem cell removes energy source from activated cell through gap junction that turns off activation switch (Quoted/modified from StemCells 2021).

Current projects

(a) Industrialization of optimized stem cell therapy
Stem cell therapy is not yet widely used as a general medical treatment due to its uncertain efficacy and extremely high cost. Our discoveries about the fundamental mechanism of action of stem cell therapies enable the development of stem cell products with reliable therapeutic effects that can be widely used in medical economics. Currently, we are conducting research for optimization of stem cell therapy, including the full elucidation of molecules that move through gap junctions, identification of gap junction inhibitor, search for substances that improve stem cell function, and establishment of quantitative evaluation methods of stem cell function.
(b) Research for small molecules and liposomes that substitute stem cell therapy
The findings about mechanism of action of stem cell therapy enable to develop small molecules and liposomes that can substitute stem cell therapy. Currently, projects of constructing functional liposomes and searching for low molecular weight compounds that can substitute for the action of stem cell therapy are ongoing.

(2) Establishment of optimized stem cell therapy for dementia
Our Achievements

(a) Stem cell transplantation to aged mice improves short term memory with enhanced neurogenesis at hippocampus
Simple aging mouse is an ideal model that accurately reflects the pathology of human dementia patients in elderly, as they show decreased motor skills, muscle mass, immunocompetence, wound-healing ability and cognitive decline. We have found that transplantation of hematopoietic stem cells to aged mice improves short term memory (Takeuchi et al. Front Aging Neurosci. 2020) with enhanced neurogenesis at hippocampus (Fig. 6) (Takeuchi et al. Front Aging Neurosci. 2022)
(b) Age-related decline in function of gap junction and its activation by stem cells.
We have found that the expression of gap junction is decreased with aging in hippocampus and stem cells transplantation increases the expression of gap junction (Takeuchi Front Aging Neurosci. 2022).

(Description of Fig. 6)

Fig. 6 Activation of neurogenesis at hippocampus by hematopoietic stem cell transplantation in aged mice

A significant number of new neurons are observed in young mice, but rarely in aged mice. The increase of new neurons was observed by hematopoietic stem cell transplantation (yellow arrow indicates one of the new neurons) (Quoted/modified from Front Aging Neurosci. 2022).

Current projects

(a) Activation of neurogenesis at hippocampus for the recovery of short term memory The most problematic symptom in patients with Alzheimer’s disease is impairment of short term memory, and recent studies showed that the neuronal cells responsible for short term memory are new neurons at hippocampus. Furthermore, it is well known that the number of new neurons at hippocampus is drastically reduced in patients with Alzheimer’s disease. Based on these findings, we have focused on the activation of neurogenesis at hippocampus by stem cell therapy (Fig. 7).
(b) Elucidation of the nature of aging
Cell-cell interaction via gap junctions has significant role in multicellular organisms. Our findings indicated that cell-cell interaction via gap junctions is significantly impaired with aging and it is activated by stem cells transplantation. These findings indicate that cell-cell interactions via gap junctions would have a significant impact on aging in multicellular organisms. We are conducting research to elucidate the nature of aging from the viewpoint of gap junctions.

(Description of Fig. 7)

Fig. 7 Our therapeutic strategy for Alzheimer’s disease

Our focus is activation of neurogenesis at hippocampus.