Secreted factors from dental pulp stem cells improve glucose intolerance in streptozotocin-induced diabetic mice by increasing pancreatic β-cell function

Takako Izumoto-Akita; Shin Tsunekawa; Akihito Yamamoto; Eita Uenishi; Kota Ishikawa; Hidetada Ogata; Atsushi Iida; Makoto Ikeniwa; Kaori Hosokawa; Yasuhiro Niwa; Ryuya Maekawa; Yuichiro Yamauchi; Yusuke Seino; Yoji Hamada; Hideharu Hibi; Hiroshi Arima; Minoru Ueda; Yutaka Oiso

doi:10.1136/bmjdrc-2015-000128

Secreted factors from dental pulp stem cells improve glucose intolerance in streptozotocin-induced diabetic mice by increasing pancreatic β-cell function

BMJ Open Diabetes Res Care. 2015 Oct 19;3(1):e000128. doi: 10.1136/bmjdrc-2015-000128. eCollection 2015.

Authors

Takako Izumoto-Akita¹, Shin Tsunekawa², Akihito Yamamoto³, Eita Uenishi², Kota Ishikawa², Hidetada Ogata², Atsushi Iida², Makoto Ikeniwa², Kaori Hosokawa², Yasuhiro Niwa², Ryuya Maekawa², Yuichiro Yamauchi², Yusuke Seino⁴, Yoji Hamada⁴, Hideharu Hibi³, Hiroshi Arima², Minoru Ueda³, Yutaka Oiso²

Affiliations

¹ Department of Endocrinology and Diabetes , Nagoya University Graduate School of Medicine , Nagoya, Aichi , Japan ; Department of Oral and Maxillofacial Surgery , Nagoya University Graduate School of Medicine , Nagoya, Aichi , Japan.
² Department of Endocrinology and Diabetes , Nagoya University Graduate School of Medicine , Nagoya, Aichi , Japan.
³ Department of Oral and Maxillofacial Surgery , Nagoya University Graduate School of Medicine , Nagoya, Aichi , Japan.
⁴ Department of Metabolic Medicine , Nagoya University Graduate School of Medicine , Nagoya, Aichi , Japan.

Abstract

Objective: Many studies have reported that stem cell transplantation promotes propagation and protection of pancreatic β-cells in streptozotocin (STZ)-induced diabetic mice without the differentiation of transplanted cells into pancreatic β-cells, suggesting that the improvement is due to a paracrine effect of the transplanted cells. We investigated the effects of factors secreted by dental pulp stem cells from human exfoliated deciduous teeth (SHED) on β-cell function and survival.

Research design and methods: Conditioned medium from SHED (SHED-CM) was collected 48 h after culturing in serum-free Dulbecco's modified Eagle's medium (DMEM). The insulin levels in SHED-CM and serum-free conditioned media from human bone marrow-derived mesenchymal stem cells (BM-CM) were undetectable. STZ-induced diabetic male C57B/6J mice were injected with DMEM as a control, SHED-CM, exendin-4 (Ex-4), or BM-CM for 14 days. Mouse pancreatic β-cell line MIN6 cells were incubated with different concentrations of STZ with SHED-CM, DMEM, Ex-4, or BM-CM for 6 h.

Results: Administration of 1 mL of SHED-CM twice a day improved glucose intolerance in STZ-induced diabetic mice and the effect continued for 20 days after the end of treatment. SHED-CM treatment increased pancreatic insulin content and β-cell mass through proliferation and an intraperitoneal glucose tolerance test revealed enhanced insulin secretion. Incubation of MIN6 cells (a mouse pancreatic β-cell line) with SHED-CM enhanced insulin secretion in a glucose concentration-dependent manner and reduced STZ-induced cell death, indicating that the amelioration of hyperglycemia was caused by the direct effects of SHED-CM on β-cell function and survival. These effects were more pronounced than with the use of Ex-4, a conventional incretin-based drug, and BM-CM, which is a medium derived from other stem cells.

Conclusions: These findings suggest that SHED-CM provides direct protection and encourages the propagation of β-cells, and has potential as a novel strategy for treatment of diabetes.

Keywords: Beta Cell Function; Beta Cell Secretion; Beta Cell(s); Proliferation.