Abstract
Despite the uniform selection criteria for the isolation of human mesenchymal stem cells (MSCs), considerable heterogeneity exists which reflects the distinct tissue origins and differences between individuals with respect to their genetic background and age. This heterogeneity is manifested by the variabilities seen in the transcriptomes, proteomes, secretomes, and epigenomes of tissue-specific MSCs. Here, we review literature on different aspects of MSC heterogeneity including the role of epigenetics and the impact of MSC heterogeneity on therapies. We then combine this with a meta-analysis of transcriptome data from distinct MSC subpopulations derived from bone marrow, adipose tissue, cruciate, tonsil, kidney, umbilical cord, fetus, and induced pluripotent stem cells derived MSCs (iMSCs). Beyond that, we investigate transcriptome differences between tissue-specific MSCs and pluripotent stem cells. Our meta-analysis of numerous MSC-related data sets revealed markers and associated biological processes characterizing the heterogeneity and the common features of MSCs from various tissues. We found that this heterogeneity is mainly related to the origin of the MSCs and infer that microenvironment and epigenetics are key drivers. The epigenomes of MSCs alter with age and this has a profound impact on their differentiation capabilities. Epigenetic modifications of MSCs are propagated during cell divisions and manifest in differentiated cells, thus contributing to diseased or healthy phenotypes of the respective tissue. An approach used to reduce heterogeneity caused by age- and tissue-related epigenetic and microenvironmental patterns is the iMSC concept: iMSCs are MSCs generated from induced pluripotent stem cells (iPSCs). During iMSC generation epigenetic and chromatin remodeling result in a gene expression pattern associated with rejuvenation thus allowing to overcome age-related shortcomings (e.g., limited differentiation and proliferation capacity). The importance of the iMSC concept is underlined by multiple clinical trials. In conclusion, we propose the use of rejuvenated iMSCs to bypass tissue- and age-related heterogeneity which are associated with native MSCs.
Highlights
Mesenchymal stem cells (MSCs) (Friedenstein et al, 1970; Caplan, 1991)/medicinal signaling cells (Caplan, 2017)/mesenchymal stromal cells (Horwitz et al, 2005) are multipotent cells with in vitro differentiation potential into mesodermal lineages such as adipocytes, chondrocytes, osteocytes, and myocytes
In a meta-analysis of transcriptome data, we compared mesenchymal stem cells (MSCs) of distinct sources which includes bone marrow (BM), adipose tissue (AT), umbilical cord (UC), cruciate, tonsil, kidney, and induced pluripotent stem cells derived MSCs (iMSCs) listed in Table 1 and Pluripotent stem cells (PSCs)
Comparing the expressed genes between iMSCs fetal, MSCs, UC-MSCs, BM-MSCs, and ATMSCs we found most genes (n = 9966) overlapping with smaller specific subsets of exclusively expressed genes (n between 29 and 558)
Summary
Mesenchymal stem cells (MSCs) (Friedenstein et al, 1970; Caplan, 1991)/medicinal signaling cells (Caplan, 2017)/mesenchymal stromal cells (Horwitz et al, 2005) are multipotent cells with in vitro differentiation potential into mesodermal lineages such as adipocytes, chondrocytes, osteocytes, and myocytes. Per definition in vitro cultured MSCs and their mesodermal differentiation potential are not comparable with the in vivo case (Keating, 2012; Caplan, 2017). A central question concerns their mechanism(s) of action in therapeutic settings: Is it based on differentiation of MSCs into a target cell type or on paracrine effects triggering surrounding cells to regenerate defective tissue? Recent publications from the Weinberg lab about epigenetic changes caused by epithelial-mesenchymal transition (EMT) distinguishing cancer stem cells (CSCs) from the non-CSC-tumor cells (Shibue and Weinberg, 2017) and by Carter and Zhao (2020) emphasize the role of epigenetics in cell fate decisions which lead to cellular heterogeneity manifested in distinct lineages and distinct differentiation and disease states
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