Identification of potential biomarkers for aging diagnosis of mesenchymal stem cells derived from the aged donors

Abstract

Background The clinical application of human bone-marrow derived mesenchymal stem cells (MSCs) for the treatment of refractory diseases has achieved remarkable results. However, there is a need for a systematic evaluation of the quality and safety of MSCs sourced from donors. In this study, we sought to assess one potential factor that might impact quality, namely the age of the donor. Methods We downloaded two data sets from each of two Gene Expression Omnibus (GEO), GSE39035 and GSE97311 databases, namely samples form young (<65 years of age) and old (>65) donor groups. Through, bioinformatics analysis and experimental validation to these retrieved data, we found that MSCs derived from aged donors can lead to differential expression of gene profiles compared with those from young donors, and potentially affect the function of MSCs, and may even induce malignant tumors. Results We identified a total of 337 differentially expressed genes (DEGs), including two upregulated and eight downregulated genes from the databases of both GSE39035 and GSE97311. We further identified 13 hub genes. Six of them, TBX15, IGF1, GATA2, PITX2, SNAI1 and VCAN, were highly expressed in many human malignancies in Human Protein Atlas database. In the MSCs in vitro senescent cell model, qPCR analysis validated that all six hub genes were highly expressed in senescent MSCs. Our findings confirm that aged donors of MSCs have a significant effect on gene expression profiles. The MSCs from old donors have the potential to cause a variety of malignancies. These TBX15, IGF1, GATA2, PITX2, SNAI1, VCAN genes could be used as potential biomarkers to diagnosis aging state of donor MSCs, and evaluate whether MSCs derived from an aged donor could be used for therapy in the clinic. Our findings provide a diagnostic basis for the clinical use of MSCs to treat a variety of diseases. Conclusions Therefore, our findings not only provide guidance for the safe and standardized use of MSCs in the clinic for the treatment of various diseases, but also provide insights into the use of cell regeneration approaches to reverse aging and support rejuvenation.

1. Introduction

Mesenchymal stem cells (MSCs) are a class of stromal cells, including multipotent stem cells, progenitors, and differentiated cells. MSCs are isolated primarily from bone marrow, adipose tissue, and umbilical cord, which have the ability to differentiate into bone, cartilage, or fat cells [1]. Current criteria for MSCs isolation yield heterogeneous, non-clonal cultures of stromal cells, including stem cells with diverse multipotential properties, committed progenitors, and differentiated cells [2, 3]. As promising new therapeutic strategy, MSCs-based therapy is under investigation for treatment of many conditions, including inflammatory, ischemic and neurodegenerative diseases [4].

Although human bone-marrow derived MSCs have both proliferative capacity and chondrogenic potential, the possibility dysfunction, accelerated aging, and malignancy are considered as potential threats to clinical applications. It is well known that the regenerative capacity of MSCs depends upon the cell source, donor age, and culture conditions [5]. For example, many studies have suggested that expansion could change the lipid composition of MSCs, such as glycosphingolipids and signaling lipids [6–9]. For example, there was evidence of differences in the glycerophospholipids profiles and in the expression of genes related to lipid metabolism and immunomodulation of MSCs from young and old donors during sequential expansion [5].

As they age, the ability of MSCs to self-renew and to differentiate gradually declines [10]. In this respect, research has suggested that MSCs play an important role in skeletal homeostasis by serving as a reservoir of osteoblast precursors and studies have linked age-related bone loss to defects in the function of MSCs including loss of proliferative and differentiat...