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


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.
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.
Takako
T
Izumoto-Akita
Department of Endocrinology and Diabetes , Nagoya University Graduate School of Medicine , Nagoya, Aichi , Japan.
Shin
S
Tsunekawa
Department of Oral and Maxillofacial Surgery , Nagoya University Graduate School of Medicine , Nagoya, Aichi , Japan.
Akihito
A
Yamamoto
Department of Endocrinology and Diabetes , Nagoya University Graduate School of Medicine , Nagoya, Aichi , Japan.
Eita
E
Uenishi
Department of Endocrinology and Diabetes , Nagoya University Graduate School of Medicine , Nagoya, Aichi , Japan.
Kota
K
Ishikawa
Department of Endocrinology and Diabetes , Nagoya University Graduate School of Medicine , Nagoya, Aichi , Japan.
Hidetada
H
Ogata
Department of Endocrinology and Diabetes , Nagoya University Graduate School of Medicine , Nagoya, Aichi , Japan.
Atsushi
A
Iida
Department of Endocrinology and Diabetes , Nagoya University Graduate School of Medicine , Nagoya, Aichi , Japan.
Makoto
M
Ikeniwa
Department of Endocrinology and Diabetes , Nagoya University Graduate School of Medicine , Nagoya, Aichi , Japan.
Kaori
K
Hosokawa
Department of Endocrinology and Diabetes , Nagoya University Graduate School of Medicine , Nagoya, Aichi , Japan.
Yasuhiro
Y
Niwa
Department of Endocrinology and Diabetes , Nagoya University Graduate School of Medicine , Nagoya, Aichi , Japan.
Ryuya
R
Maekawa
Department of Endocrinology and Diabetes , Nagoya University Graduate School of Medicine , Nagoya, Aichi , Japan.
Yuichiro
Y
Yamauchi
Department of Metabolic Medicine , Nagoya University Graduate School of Medicine , Nagoya, Aichi , Japan.
Yusuke
Y
Seino
Department of Metabolic Medicine , Nagoya University Graduate School of Medicine , Nagoya, Aichi , Japan.
Yoji
Y
Hamada
Department of Oral and Maxillofacial Surgery , Nagoya University Graduate School of Medicine , Nagoya, Aichi , Japan.
Hideharu
H
Hibi
Department of Endocrinology and Diabetes , Nagoya University Graduate School of Medicine , Nagoya, Aichi , Japan.
Hiroshi
H
Arima
Department of Oral and Maxillofacial Surgery , Nagoya University Graduate School of Medicine , Nagoya, Aichi , Japan.
Minoru
M
Ueda
Department of Endocrinology and Diabetes , Nagoya University Graduate School of Medicine , Nagoya, Aichi , Japan.
Yutaka
Y
Oiso
Beta Cell Function; Beta Cell Secretion; Beta Cell(s); Proliferation