Transplantation of human dental pulp stem cells in streptozotocin-induced diabetic rats

Abstract

Type 1 diabetes mellitus (T1DM) is a chronic metabolic disease caused by the destruction of pancreatic β-cells. Human dental pulp stem cells represent a promising source for cell-based therapies, owing to their easy, minimally invasive surgical access, and high proliferative capacity. It was reported that human dental pulp stem cells can differentiate into a pancreatic cell lineage in vitro; however, few studies have investigated their effects on diabetes. Our study aimed to investigate the therapeutic potential of intravenous and intrapancreatic transplantation of human dental pulp stem cells in a rat model of streptozotocin-induced type 1 diabetes. Forty Sprague Dawley male rats were randomly categorized into four groups: control, diabetic (STZ), intravenous treatment group (IV), and intrapancreatic treatment group (IP). Human dental pulp stem cells (1 × 106 cells) or vehicle were injected into the pancreas or tail vein 7 days after streptozotocin injection. Fasting blood glucose levels were monitored weekly. Glucose tolerance test, rat and human serum insulin and C-peptide, pancreas histology, and caspase-3, vascular endothelial growth factor, and Ki67 expression in pancreatic tissues were assessed 28 days post-transplantation. We found that both IV and IP transplantation of human dental pulp stem cells reduced blood glucose and increased levels of rat and human serum insulin and C-peptide. The cells engrafted and survived in the streptozotocin-injured pancreas. Islet-like clusters and scattered human dental pulp stem cells expressing insulin were observed in the pancreas of diabetic rats with some difference in the distribution pattern between the two injection routes. RT-PCR analyses revealed the expression of the human-specific pancreatic β-cell genes neurogenin 3 (NGN3), paired box 4 (PAX4), glucose transporter 2 (GLUT2), and insulin in the pancreatic tissues of both the IP and IV groups. In addition, the transplanted cells downregulated the expression of caspase-3 and upregulated the expression of vascular endothelial growth factor and Ki67, suggesting that the injected cells exerted pro-angiogenetic and antiapoptotic effects, and promoted endogenous β-cell replication. Our study is the first to show that human dental pulp stem cells can migrate and survive within streptozotocin-injured pancreas, and induce antidiabetic effects through the differentiation and replacement of lost β-cells and paracrine-mediated pancreatic regeneration. Thus, human dental pulp stem cells may have therapeutic potential to treat patients with long term T1DM.

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Abbreviations

hDPSCs:

Human dental pulp stem cells

STZ:

Streptozotocin

T1DM:

Type 1 diabetes mellitus

IV:

Intravenous

IP:

Intrapancreatic

NGN3:

Neurogenin 3

PAX4:

Paired box 4

GLUT2:

Glucose transporter 2

VEGF:

Vascular endothelial growth factor

MSCs:

Mesenchymal stem cells

FBS:

Fetal bovine serum

FBS/PBS:

Fetal bovine serum/phosphate-buffered saline

STRO-1:

Stromal precursor antigen-1

RT-PCR:

Reverse transcription-polymerase chain reaction

H&E:

Hematoxylin and eosin

RT:

Room temperature

ANOVA:

One-way or two-way analysis of variance

BM-MSCs:

Bone marrow-derived MSCs

MHC-1:

Human major histocompatibility complex 1

ICCs:

Islet-like cell clusters

SHED:

Stem cells from pulps of human exfoliated deciduous teeth

HMECs:

Human mammary epithelial cells

PI3K:

Phosphoinositide 3-kinase

Reg I alpha:

Regenerating gene protein I alpha

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Acknowledgement

This research was funded by the Deanship of Scientific Research at Princess Nourah bint Abdulrahman University through the Fast-track Research Funding Program.

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Correspondence to Gehan El-Akabawy.

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El-Kersh, A.O.F.O., El-Akabawy, G. & Al-Serwi, R.H. Transplantation of human dental pulp stem cells in streptozotocin-induced diabetic rats. Anat Sci Int (2020). https://doi.org/10.1007/s12565-020-00550-2

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Keywords

  • Human dental pulp stem cells
  • Transplantation
  • Streptozotocin
  • Rat
  • Type 1 diabetes mellitus