Abstract
This study aimed to investigate the effects of the human macrophage (MP) secretome in cellular xenograft rejection. The role of human nucleoside diphosphate kinase A (hNME1), from the secretome of MPs involved in the neuronal differentiation of miniature pig adipose tissue-derived mesenchymal stem cells (mp AD-MSCs), was evaluated by proteomic analysis. Herein, we first demonstrate that hNME1 strongly binds to porcine ST8 alpha-N-acetyl-neuraminide alpha-2,8-sialyltransferase 1 (pST8SIA1), which is a ganglioside GD3 synthase. When hNME1 binds with pST8SIA1, it induces degradation of pST8SIA1 in mp AD-MSCs, thereby inhibiting the expression of ganglioside GD3 followed by decreased neuronal differentiation of mp AD-MSCs. Therefore, we produced nanobodies (NBs) named NB-hNME1 that bind to hNME1 specifically, and the inhibitory effect of NB-hNME1 was evaluated for blocking the binding between hNME1 and pST8SIA1. Consequently, NB-hNME1 effectively blocked the binding of hNME1 to pST8SIA1, thereby recovering the expression of ganglioside GD3 and neuronal differentiation of mp AD-MSCs. Our findings suggest that mp AD-MSCs could be a potential candidate for use as an additive, such as an immunosuppressant, in stem cell transplantation.
Highlights
As human life expectancy increases, the number of patients with terminal organ failure, such as that due to chronic intractable neurological diseases, continues to increase.Organ transplantation or cell therapy is an effective treatment approach for terminal organ failure patients
We used phorbol 12-myristate 13-acetate (PMA) to induce differentiation of human monocyte U937 cells into an MP-like phenotype, and the differentiated MPs showed expression of cluster of differentiation molecule 14 (CD14) and integrin alpha M (CD11b), which are MP surface markers
Before determining whether NME1 controls ganglioside GD3 of mp AD-MSCs, 7 of we quantitatively evaluated NME1 secreted by MPs and its effects on the proliferation and neuronal differentiation of mp AD-MSCs using recombinant hNME1 proteins
Summary
As human life expectancy increases, the number of patients with terminal organ failure, such as that due to chronic intractable neurological diseases, continues to increase. Organ transplantation or cell therapy (stem cell transplantation) is an effective treatment approach for terminal organ failure patients. For successful clinical transplants, the imbalance between the supply and demand for human organs must be resolved [1]. The continual shortage of human organs or cells is stimulating research in the field of xenotransplantation, and pigs are currently considered the most suitable potential source of organs or cells. The scientific barrier has been somewhat resolved owing to the introduction of organ-source miniature pigs produced by genetic engineering and the availability and application of novel immunosuppressive agents [2,3]. Through various studies, transplant research has developed rapidly in recent years, and
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