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. 2014 Feb;26(1):1-10.
doi: 10.5021/ad.2014.26.1.1. Epub 2014 Feb 17.

Synergistic effect of bone marrow-derived mesenchymal stem cells and platelet-rich plasma in streptozotocin-induced diabetic rats

Zhenzhen Lian  1 , Xiaojing Yin  2 , Hua Li  1 , Lili Jia  1 , Xiuzhen He  1 , Yongbo Yan  1 , Naihua Liu  1 , Kayiu Wan  1 , Xiaokun Li  1 , Shaoqiang Lin  1
Affiliations

Synergistic effect of bone marrow-derived mesenchymal stem cells and platelet-rich plasma in streptozotocin-induced diabetic rats

Zhenzhen Lian et al. Ann Dermatol. 2014 Feb.

Abstract

Background: Diabetic wounds are a major clinical challenge, because minor skin wounds can lead to chronic, unhealed ulcers and ultimately result in infection, gangrene, or even amputation. Studies on bone marrow derived mesenchymal stem cells (BMSCs) and a series of growth factors have revealed their many benefits for wound healing and regeneration. Platelet-rich plasma (PRP) may improve the environment for BMSC development and differentiation. However, whether combined use of BMSCs and PRP may be more effective for accelerating diabetic ulcer healing remains unclear.

Objective: We investigated the efficacy of BMSCs and PRP for the repair of refractory wound healing in a diabetic rat model.

Methods: Forty-eight rats with diabetes mellitus induced by streptozotocin were divided into four groups: treatment with BMSCs plus PRP, BMSCs alone, PRP alone, phosphate buffered saline. The rate of wound closure was quantified. A histopathological study was conducted regarding wound depth and the skin edge at 7, 14, and 28 days after surgery.

Results: Wound healing rates were significantly higher in the BMSC plus PRP group than in the other groups. The immunohistochemistry results showed that the expression of platelet/endothelial cell adhesion molecule 1, proliferating cell nuclear antigen, and transforming growth factor-β1 increased significantly in the BMSC plus PRP group compared to the other treatment groups. On day 7, CD68 expression increased significantly in the wounds of the BMSC plus PRP group, but decreased markedly at day 14 compared to the controls.

Conclusion: The combination of BMSCs and PRP aids diabetic wound repair and regeneration.

Keywords: Bone marrow-derived mesenchymal stem cell; Diabetes mellitus; Platelet-rich plasma; Wounds.

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Figures

Fig. 1
Fig. 1
Flow cytometry analysis of cultured bone marrow-derived mesenchymal stem cells. The samples had no surface marker expression for hematopoietic stem cells (CD45 [2.0%] and CD11b/c [1.7%]), but highly expressed the surface markers for mesenchymal stem cells (CD29 [98.8%] and CD90 [98.4%]). SD: side scatter.
Fig. 2
Fig. 2
Treatment with bone marrow-derived mesenchymal stem cells (BMSCs) plus platelet-rich plasma (PRP) improves wound healing in diabetic rats. (A) Representative photographs of skin wounds from each group at various time points after surgery. (B) Wound closure rates. Results represent the mean±standard error; n=3 rats. *p<0.05 vs. PRP, *p<0.05 vs. BMSCs.
Fig. 3
Fig. 3
Masson's trichrome staining (A~D: ×40) and H&E staining (E~H: ×20) of wounded skin sections. Results from a representative animal of four studied in each group are shown. BMSCs: bone marrow-derived mesenchymal stem cells, PRP: platelet-rich plasma.
Fig. 4
Fig. 4
Effects of bone marrow-derived mesenchymal stem cells (BMSCs) and platelet-rich plasma (PRP) on wound vascularity. (A) Platelet/endothelial cell adhesion molecule 1 staining of blood vessels in the wound bed (×40). a: Control, b: BMSCs, c: PRP, d: BMSCs plus PRP. Results from a representative animal of four studied from each group are shown. (B) Quantification of vessel density. Bar graph shows mean±standard error in each group. HPF: high power field. *p<0.05 vs. control, **p<0.05 vs. PRP, **p<0.05 vs. BMSCs.
Fig. 5
Fig. 5
Assessment of cell proliferation in wounds by proliferating cell nuclear antigen (PCNA). (A) PCNA staining (brown) of proliferating cells in the wound bed (×40). Results from a representative animal of four studied in each group are shown. (B) Quantification of PCNA-positive cells. HPF: high power field. *p<0.05 vs. control, **p<0.05 vs. platelet-rich plasma (PRP), **p<0.05 vs. bone marrow-derived mesenchymal stem cells (BMSCs). (C) The PCNA protein was detected by Western blot. Glyceraldehyde 3-phosphate dehydrogenase (GAPDH) was used as the loading control. (D) The column figure shows the normalized optical density of PCNA/GAPDH. Columns represent mean±standard error of three independent experiments. *p<0.0001 vs. control, **p<0.001 vs. PRP, **p<0.0001 vs. BMSCs.
Fig. 6
Fig. 6
Effect of treatment with bone marrow-derived mesenchymal stem cells (BMSCs) and platelet-rich plasma (PRP) on the inflammatory response during wound healing. (A) CD68 staining (brown) of proliferating cells in the wound bed (×40). Results from a representative animal of four studied in each group are shown. (B) Quantification of CD68-positive cells. HPF: high power field. *p<0.05 vs. control, **p<0.05 vs. PRP, **p<0.05 vs. BMSCs. (C) CD68 protein level was detected by Western blot, and glyceraldehyde 3-phosphate dehydrogenase (GAPDH) was used as the loading control. (D) The column figure shows the normalized optical density of CD68/GAPDH. Columns represent mean±standard error of three independent experiments. *p<0.05 vs. control, **p<0.05 vs. PRP, **p<0.05 vs. BMSCs.
Fig. 7
Fig. 7
Effect of treatment with bone marrow-derived mesenchymal stem cells (BMSCs) and platelet-rich plasma (PRP) on transforming growth factor-β1 (TGF-β1) level. (A) TGF-β1 staining (brown) of proliferating cells in the wound bed (×40). a: Control, b: BMSCs, c: PRP, d: BMSCs plus PRP. Results from a representative animal out of four studied in each group are shown. (B) Quantification of TGF-β1-positive cells. HPF: high power field. *p<0.05 vs. control, **p<0.05 vs. PRP, **p<0.05 vs. BMSCs. (C) TGF-β1 protein level was detected by Western blot. Glyceraldehyde 3-phosphate dehydrogenase (GAPDH) was used as the loading control. (D) The column figure shows the normalized optical density of TGF-β1/GAPDH. Columns represent mean±standard error of three independent experiments. *p<0.05 vs. control, **p<0.05 compared to any other group.
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