Eri Takematsu

All Publications

• Ultrasensitive and multiplexed tracking of single cells using whole-body PET/CT. Science advances Nguyen, H. T., Das, N., Ricks, M., Zhong, X., Takematsu, E., Wang, Y., Ruvalcaba, C., Mehadji, B., Roncali, E., Chan, C. K., Pratx, G. 2024; 10 (24): eadk5747

  Abstract

  In vivo molecular imaging tools are crucially important for elucidating how cells move through complex biological systems; however, achieving single-cell sensitivity over the entire body remains challenging. Here, we report a highly sensitive and multiplexed approach for tracking upward of 20 single cells simultaneously in the same subject using positron emission tomography (PET). The method relies on a statistical tracking algorithm (PEPT-EM) to achieve a sensitivity of 4 becquerel per cell and a streamlined workflow to reliably label single cells with over 50 becquerel per cell of 18F-fluorodeoxyglucose (FDG). To demonstrate the potential of the method, we tracked the fate of more than 70 melanoma cells after intracardiac injection and found they primarily arrested in the small capillaries of the pulmonary, musculoskeletal, and digestive organ systems. This study bolsters the evolving potential of PET in offering unmatched insights into the earliest phases of cell trafficking in physiological and pathological processes and in cell-based therapies.

  View details for DOI 10.1126/sciadv.adk5747

  View details for PubMedID 38875333

  View details for PubMedCentralID PMC11177933

• Transmembrane stem factor nanodiscs enhanced revascularization in a hind limb ischemia model in diabetic, hyperlipidemic rabbits. Scientific reports Takematsu, E., Massidda, M., Howe, G., Goldman, J., Felli, P., Mei, L., Callahan, G., Sligar, A. D., Smalling, R., Baker, A. B. 2024; 14 (1): 2352

  Abstract

  Therapies to revascularize ischemic tissue have long been a goal for the treatment of vascular disease and other disorders. Therapies using stem cell factor (SCF), also known as a c-Kit ligand, had great promise for treating ischemia for myocardial infarct and stroke, however clinical development for SCF was stopped due to toxic side effects including mast cell activation in patients. We recently developed a novel therapy using a transmembrane form of SCF (tmSCF) delivered in lipid nanodiscs. In previous studies, we demonstrated tmSCF nanodiscs were able to induce revascularization of ischemia limbs in mice and did not activate mast cells. To advance this therapeutic towards clinical application, we tested this therapy in an advanced model of hindlimb ischemia in rabbits with hyperlipidemia and diabetes. This model has therapeutic resistance to angiogenic therapies and maintains long term deficits in recovery from ischemic injury. We treated rabbits with local treatment with tmSCF nanodiscs or control solution delivered locally from an alginate gel delivered into the ischemic limb of the rabbits. After eight weeks, we found significantly higher vascularity in the tmSCF nanodisc-treated group in comparison to alginate treated control as quantified through angiography. Histological analysis also showed a significantly higher number of small and large blood vessels in the ischemic muscles of the tmSCF nanodisc treated group. Importantly, we did not observe inflammation or mast cell activation in the rabbits. Overall, this study supports the therapeutic potential of tmSCF nanodiscs for treating peripheral ischemia.

  View details for DOI 10.1038/s41598-024-52888-6

  View details for PubMedID 38287067

  View details for PubMedCentralID 3654492

• Thumb Osteoarthritis: Stem Cell Activation, Niche Augmentation and Tissue Regeneration Murphy, M., Takematsu, E., Koepke, L., Tong, X., Butler, G., Ambrosi, T., Hoover, M., Wang, Y., Zhao, L., Wong, J., Reid, A., Longaker, M., Chan, C. MARY ANN LIEBERT, INC. 2023

  View details for Web of Science ID 001126807000330

• Thumb Osteoarthritis: Stem Cell Activation, Niche Augmentation and Tissue Regeneration Murphy, M., Takematsu, E., Koepke, L., Tong, X., Butler, G., Ambrosi, T., Hoover, M., Wang, Y., Zhao, L., Wong, J., Reid, A., Longaker, M., Chant, C. MARY ANN LIEBERT, INC. 2023

  View details for Web of Science ID 001057609600337

• Purification and functional characterization of novel human skeletal stem cell lineages. Nature protocols Hoover, M. Y., Ambrosi, T. H., Steininger, H. M., Koepke, L. S., Wang, Y., Zhao, L., Murphy, M. P., Alam, A. A., Arouge, E. J., Butler, M. G., Takematsu, E., Stavitsky, S. P., Hu, S., Sahoo, D., Sinha, R., Morri, M., Neff, N., Bishop, J., Gardner, M., Goodman, S., Longaker, M., Chan, C. K. 2023

  Abstract

  Human skeletal stem cells (hSSCs) hold tremendous therapeutic potential for developing new clinical strategies to effectively combat congenital and age-related musculoskeletal disorders. Unfortunately, refined methodologies for the proper isolation of bona fide hSSCs and the development of functional assays that accurately recapitulate their physiology within the skeleton have been lacking. Bone marrow-derived mesenchymal stromal cells (BMSCs), commonly used to describe the source of precursors for osteoblasts, chondrocytes, adipocytes and stroma, have held great promise as the basis of various approaches for cell therapy. However, the reproducibility and clinical efficacy of these attempts have been obscured by the heterogeneous nature of BMSCs due to their isolation by plastic adherence techniques. To address these limitations, our group has refined the purity of individual progenitor populations that are encompassed by BMSCs by identifying defined populations of bona fide hSSCs and their downstream progenitors that strictly give rise to skeletally restricted cell lineages. Here, we describe an advanced flow cytometric approach that utilizes an extensive panel of eight cell surface markers to define hSSCs; bone, cartilage and stromal progenitors; and more differentiated unipotent subtypes, including an osteogenic subset and three chondroprogenitors. We provide detailed instructions for the FACS-based isolation of hSSCs from various tissue sources, in vitro and in vivo skeletogenic functional assays, human xenograft mouse models and single-cell RNA sequencing analysis. This application of hSSC isolation can be performed by any researcher with basic skills in biology and flow cytometry within 1-2 days. The downstream functional assays can be performed within a range of 1-2 months.

  View details for DOI 10.1038/s41596-023-00836-5

  View details for PubMedID 37316563

  View details for PubMedCentralID 6568007

• Optimizing Delivery of Therapeutic Growth Factors for Bone and Cartilage Regeneration. Gels (Basel, Switzerland) Takematsu, E., Murphy, M., Hou, S., Steininger, H., Alam, A., Ambrosi, T. H., Chan, C. K. 2023; 9 (5)

  Abstract

  Bone- and cartilage-related diseases, such as osteoporosis and osteoarthritis, affect millions of people worldwide, impairing their quality of life and increasing mortality. Osteoporosis significantly increases the bone fracture risk of the spine, hip, and wrist. For successful fracture treatment and to facilitate proper healing in the most complicated cases, one of the most promising methods is to deliver a therapeutic protein to accelerate bone regeneration. Similarly, in the setting of osteoarthritis, where degraded cartilage does not regenerate, therapeutic proteins hold great promise to promote new cartilage formation. For both osteoporosis and osteoarthritis treatments, targeted delivery of therapeutic growth factors, with the aid of hydrogels, to bone and cartilage is a key to advance the field of regenerative medicine. In this review article, we propose five important aspects of therapeutic growth factor delivery for bone and cartilage regeneration: (1) protection of protein growth factors from physical and enzymatic degradation, (2) targeted growth factor delivery, (3) controlling GF release kinetics, (4) long-term stability of regenerated tissues, and (5) osteoimmunomodulatory effects of therapeutic growth factors and carriers/scaffolds.

  View details for DOI 10.3390/gels9050377

  View details for PubMedID 37232969

• Transmembrane stem cell factor protein therapeutics enhance revascularization in ischemia without mast cell activation NATURE COMMUNICATIONS Takematsu, E., Massidda, M., Auster, J., Chen, P., Im, B., Srinath, S., Canga, S., Singh, A., Majid, M., Sherman, M., Dunn, A., Graham, A., Martin, P., Baker, A. B. 2022; 13 (1): 2497

  Abstract

  Stem cell factor (SCF) is a cytokine that regulates hematopoiesis and other biological processes. While clinical treatments using SCF would be highly beneficial, these have been limited by toxicity related to mast cell activation. Transmembrane SCF (tmSCF) has differential activity from soluble SCF and has not been explored as a therapeutic agent. We created novel therapeutics using tmSCF embedded in proteoliposomes or lipid nanodiscs. Mouse models of anaphylaxis and ischemia revealed the tmSCF-based therapies did not activate mast cells and improved the revascularization in the ischemic hind limb. Proteoliposomal tmSCF preferentially acted on endothelial cells to induce angiogenesis while tmSCF nanodiscs had greater activity in inducing stem cell mobilization and recruitment to the site of injury. The type of lipid nanocarrier used altered the relative cellular uptake pathways and signaling in a cell type dependent manner. Overall, we found that tmSCF-based therapies can provide therapeutic benefits without off target effects.

  View details for DOI 10.1038/s41467-022-30103-2

  View details for Web of Science ID 000791826000010

  View details for PubMedID 35523773

  View details for PubMedCentralID PMC9076913

• Genome wide analysis of gene expression changes in skin from patients with type 2 diabetes PLOS ONE Takematsu, E., Spencer, A., Auster, J., Chen, P., Graham, A., Martin, P., Baker, A. B. 2020; 15 (2): e0225267

  Abstract

  Non-healing chronic ulcers are a serious complication of diabetes and are a major healthcare problem. While a host of treatments have been explored to heal or prevent these ulcers from forming, these treatments have not been found to be consistently effective in clinical trials. An understanding of the changes in gene expression in the skin of diabetic patients may provide insight into the processes and mechanisms that precede the formation of non-healing ulcers. In this study, we investigated genome wide changes in gene expression in skin between patients with type 2 diabetes and non-diabetic patients using next generation sequencing. We compared the gene expression in skin samples taken from 27 patients (13 with type 2 diabetes and 14 non-diabetic). This information may be useful in identifying the causal factors and potential therapeutic targets for the prevention and treatment of diabetic related diseases.

  View details for DOI 10.1371/journal.pone.0225267

  View details for Web of Science ID 000535227900006

  View details for PubMedID 32084158

  View details for PubMedCentralID PMC7034863

• In vivo osteoconductivity of surface modified Ti-29Nb-13Ta-4.6Zr alloy with low dissolution of toxic trace elements. PloS one Takematsu, E., Noguchi, K., Kuroda, K., Ikoma, T., Niinomi, M., Matsushita, N. 2018; 13 (1): e0189967

  Abstract

  Simulated Body Fluid (SBF) has served as a useful standard to check the bioactivity of implant materials for years. However, it is not perfectly able to imitate human serum; sometimes disparities between the SBF test and animal test were confirmed. Therefore, to ensure the reliability of the results of the SBF test obtained from our previous study, an animal study was performed to check osteoconductivity of surface modified implant materials. Three types of solution processes, hydrothermal (H), electrochemical (E), and hydrothermal-electrochemical (HE), were performed on the Ti-29Nb-13Ta-4.6Zr alloy (TNTZ) to improve its bioactivity, and their bioactivities were measured in vivo using bone-implant contacts (BICs). BICs of the HE- and H-treated samples were significantly higher than that of the control. Metal ion diffusion towards the bone was also evaluated to examine the adverse effect of metal ions. No metal ion diffusion was observed, indicating the safety of our solution processed implant materials.

  View details for DOI 10.1371/journal.pone.0189967

  View details for PubMedID 29342150

  View details for PubMedCentralID PMC5771579

• Adhesive strength of bioactive oxide layers fabricated on TNTZ alloy by three different alkali-solution treatments. Journal of the mechanical behavior of biomedical materials Takematsu, E., Cho, K., Hieda, J., Nakai, M., Katsumata, K., Okada, K., Niinomi, M., Matsushita, N. 2016; 61: 174-181

  Abstract

  Bioactive oxide layers were fabricated on Ti-29Nb-13Ta-4.6Zr alloy (TNTZ) by three different alkali solution treatments: hydrothermal (H), electrochemical (E), and hydrothermal-electrochemical (HE). The adhesive strength of the oxide layer to the TNTZ substrate was measured to determine whether this process achieves sufficient adhesive strength for implant materials. Samples subjected to the HE process, in which a current of 15mA/cm(2) was applied at 90°C for 1h (HE90-1h), exhibited a comparatively higher adhesive strength of approximately 18MPa while still maintaining a sufficiently high bioactivity. Based on these results, an oxide layer fabricated on TNTZ by HE90-1h is considered appropriate for practical biomaterial application, though thicker oxide layers with many cracks can lead to a reduced adhesive strength.

  View details for DOI 10.1016/j.jmbbm.2015.12.046

  View details for PubMedID 26866453

• Bioactive surface modification of Ti-29Nb-13Ta-4.6Zr alloy through alkali solution treatments. Materials science & engineering. C, Materials for biological applications Takematsu, E., Katsumata, K., Okada, K., Niinomi, M., Matsushita, N. 2016; 62: 662-7

  Abstract

  Bioactive surface modification of Ti-29Nb-13Ta-4.6Zr alloy (TNTZ) was performed through three different alkali solution treatments, including the electrochemical (E), hydrothermal (H), and hydrothermal-electrochemical (HE) processes; all of the processes lead to the formation of sodium-contained amorphous titanium oxide layers on TNTZ samples. The TNTZ samples subjected to the E, H, and HE processes exhibit a flat surface, smooth and fine mesh-like structure surface, and rough mesh-like structure surface, respectively. In the bioactive test, namely, simulated body fluid test, apatite inductivity increases as the surface morphology becomes rough. The order of inductivity for the three processes was HE>H>E. The surface chemical composition also affects the apatite induction ability. The surface with fewer niobium species exhibits better apatite inductivity.

  View details for DOI 10.1016/j.msec.2016.01.041

  View details for PubMedID 26952470