{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T16:57:50Z","timestamp":1790269070238,"version":"4.1.0"},"reference-count":160,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,9,16]],"date-time":"2021-09-16T00:00:00Z","timestamp":1631750400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cell Dev. Biol."],"abstract":"<jats:p>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.<\/jats:p>","DOI":"10.3389\/fcell.2021.717772","type":"journal-article","created":{"date-parts":[[2021,9,16]],"date-time":"2021-09-16T05:16:57Z","timestamp":1631769417000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":60,"title":["Human Induced Pluripotent Stem Cell-Derived Mesenchymal Stem Cells Acquire Rejuvenation and Reduced Heterogeneity"],"prefix":"10.3389","volume":"9","author":[{"given":"Wasco","family":"Wruck","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nina","family":"Graffmann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lucas-Sebastian","family":"Spitzhorn","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James","family":"Adjaye","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,9,16]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1038\/bcj.2015.73","article-title":"Bispecific antibody releasing-mesenchymal stromal cell machinery for retargeting T cells towards acute myeloid leukemia blasts.","volume":"5","author":"Aliperta","year":"2015","journal-title":"Blood Cancer J."},{"key":"B2","doi-asserted-by":"publisher","first-page":"204","DOI":"10.1016\/j.omtm.2020.01.005","article-title":"Therapeutic mesenchymal stromal cells for immunotherapy and for gene and drug delivery.","volume":"16","author":"Almeida-Porada","year":"2020","journal-title":"Mol. 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