Abstract
BackgroundDiabetes can cause extensive enteric nervous system (ENS) injuries and gastrointestinal motility disorder. In developing possible treatments, researchers have engaged in tissue regeneration engineering with the very promising bone marrow-derived mesenchymal stem cells (BMSCs). However, BMSCs have poor homing ability to the targeted tissues after intravenous injection. Thus, we aimed to investigate whether enhancing the expression of E-selectin ligand on BMSCs could improve their homing ability and subsequently influence their role in ENS remodeling in diabetic mice.MethodsFirst, we constructed the fucosylation modification of CD44 on BMSCs through a fucosyltransferase VII (FTVII) system to generate a Hematopoietic Cell E-/L-selectin Ligand (HCELL) property, a fucosylated sialyllactosaminyl glycovariant of CD44 that potently binds E-selectin. Next, FTVII-modified and unmodified BMSCs labeled with green fluorescent protein (GFP) were injected into diabetic mice through the tail vein to compare their homing ability to the gastrointestinal tract and their effect on ENS remodeling, respectively. A bioluminescent imaging system was used to evaluate the homing ability of GFP-labeled BMSCs with and without FTVII modification, to the gastrointestinal tract. Gastrointestinal motility was assessed by gastrointestinal transient time, defecation frequency, stool water content and colon strips contractility. Immunofluorescence staining and western blotting were used to assess the expression levels of protein gene product 9.5 (PGP9.5), glial fibrillary acidic protein (GFAP) and glial cell line-derived neurotrophic factor (GDNF).ResultsThe FTVII-mediated α(1,3)-fucosylation modification of CD44 on BMSCs generated a HCELL property. Bioluminescent imaging assays showed that FTVII-modified BMSCs had enhanced homing ability to gastrointestinal tract, mainly to the colon, 24 h after injection through the tail vein. Compared with diabetic mice, FTVII-modified BMSCs significantly promoted the gastrointestinal motility and the ENS remodeling, including intestinal peristalsis (P < 0.05), increased feces excretion (P < 0.05) and the water content of the feces (P < 0.05), restored the spontaneous contraction of the colon (P < 0.05), and upregulated the protein expression levels of PGP9.5 (P < 0.01), GFAP (P < 0.001), and GDNF (P < 0.05), while unmodified BMSCs did not (P > 0.05).ConclusionsCD44 fucosylation modification on murine BMSCs promotes homing ability to the gastrointestinal tract and ENS remodeling in diabetic mice.
Highlights
The enteric nervous system (ENS), as an independent network of neurons and glial cells, is the most important direct factor in the regulation of gastrointestinal motility [1]
fucosyltransferase VII (FTVII)‐mediated α(1,3)‐exofucosylation of bone marrow-derived mesenchymal stem cells (BMSCs) converted cell surface CD44 into Hematopoietic Cell E-/L-selectin Ligand (HCELL) The flow cytometry data showed that CD44 was highly expressed in BMSCs, while BMSCs did not natively express E-selectin ligand (Fig. 1A, B)
Fucosylation modification enhanced the migration of BMSCs to the gastrointestinal tract To evaluate the degree of migration of FTVII-modified and unmodified BMSCs to gastrointestinal tract after systemic intravenous administration in diabetic mice, green fluorescent protein (GFP)-labelled FTVII-modified and unmodified BMSCs were intravenously injected, respectively
Summary
The enteric nervous system (ENS), as an independent network of neurons and glial cells, is the most important direct factor in the regulation of gastrointestinal motility [1]. Bone marrow-derived mesenchymal stem cells (BMSCs) have been shown to promote nerve repair in a variety of nerve injury models. BMSCs pretreated with brain-derived neurotrophic factor combined with chondroitinase transplantation at the site of spinal cord transection injury in rats can significantly promote motor function recovery and spinal axon regeneration [10]. In the rat model of sciatic nerve transection injury, Mohammadi R et al found that the combination of local BMSCs grafted with pulsed electromagnetic fields can promote axon regeneration and recovery of transection nerve function [11]. Researchers have engaged in tissue regeneration engineering with the very promising bone marrow-derived mesenchymal stem cells (BMSCs). We aimed to investigate whether enhancing the expression of E-selectin ligand on BMSCs could improve their homing ability and subsequently influence their role in ENS remodeling in diabetic mice
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