Strong Transcriptional Signature of Mesenchymal Stromal Cells from Perinatal Tissues Compared with Adult Bone Marrow Sources Independent of Donors or Culture Conditions
Restricted accessResearch articleFirst published online November, 2025
Strong Transcriptional Signature of Mesenchymal Stromal Cells from Perinatal Tissues Compared with Adult Bone Marrow Sources Independent of Donors or Culture Conditions
Mesenchymal stromal cells (MSCs) are currently used in clinical practice as a therapeutic agent for immunomodulation and tissue repair. They are found in all supporting tissues, including perinatal tissues such as umbilical cord and amniotic membranes (amnion and chorion). Perinatal tissues have attracted interest due to their availability, minimal ethical and legal concerns, and high banking potential for allogeneic applications. Many studies have compared the efficacy of MSCs from different sources, without reaching a consensus on the most effective to use in a given clinical situation. This study compared the transcriptomic signatures of MSCs derived from adult bone marrow (BM-MSCs)—the reference source most widely used in clinical trials—with those of perinatal MSCs (P-MSCs). Our data were analyzed jointly with three independent transcriptome datasets. Unsupervised principal component analysis revealed a major stratification according to tissue origin, accounting for 16.6% of the total transcriptomic variance, without any detectable bias from batch effects or cell culture procedures. Supervised differential expressed gene analysis between BM and perinatal samples revealed 819 genes presenting differential expression. Gene Set Enrichment Analysis highlighted that adult BM-MSCs are implicated in adipogenesis and osteoblast differentiation, whereas P-MSCs upregulated gene sets implicated in cell cycle regulation, functions classically described in the literature. Among the different sources of variability, we showed that perinatal tissues have a strongly distinct transcriptional signature compared with adult BM, independent of the production center or the culture conditions used. The in-depth study of transcript profiles therefore seems to remain a valuable and robust characterization tool for cell therapy banking.
PeltzerJ, MontespanF, ThepenierC, et al.Heterogeneous functions of perinatal mesenchymal stromal cells require a preselection before their banking for clinical use. Stem Cells Dev, 2015; 24:329–344.
5.
ViswanathanS, ShiY, GalipeauJ, et al.Mesenchymal stem versus stromal cells: International Society for Cell & Gene Therapy (ISCT®) Mesenchymal Stromal Cell committee position statement on nomenclature. Cytotherapy, 2019; 21:1019–1024.
6.
PappaKI, AnagnouNP. Novel sources of fetal stem cells: Where do they fit on the developmental continuum? Regen Med, 2009; 4:423–433.
7.
MacrinD, JosephJP, PillaiAA, et al.Eminent sources of adult mesenchymal stem cells and their therapeutic imminence. Stem Cell Rev Rep, 2017; 13:741–756.
8.
WrightA, Arthaud-DayML, WeissML. Therapeutic use of mesenchymal stromal cells: The need for inclusive characterization guidelines to accommodate all tissue sources and species. Front Cell Dev Biol, 2021; 9:632717. Available from: https://www.frontiersin.org/articles/10.3389/fcell.2021.632717
9.
PhinneyDG. Functional heterogeneity of mesenchymal stem cells: Implications for cell therapy. J Cell Biochem, 2012; 113:2806–2812.
10.
LiuS, de CastroLF, JinP, et al.Manufacturing differences affect human bone marrow stromal cell characteristics and function: Comparison of production methods and products from multiple centers. Sci Rep, 2017; 7:46731.
11.
DominiciM, Le BlancK, MuellerI, et al.Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy, 2006; 8:315–317.
12.
GalipeauJ. The mesenchymal stromal cells dilemma—does a negative phase III trial of random donor mesenchymal stromal cells in steroid-resistant graft-versus-host disease represent a death knell or a bump in the road? Cytotherapy, 2013; 15:2–8.
13.
AlhattabD, JamaliF, AliD, et al.An insight into the whole transcriptome profile of four tissue-specific human mesenchymal stem cells. Regen Med, 2019; 14:841–865.
14.
SacchettiB, FunariA, RemoliC, et al.No identical “mesenchymal stem cells” at different times and sites: Human committed progenitors of distinct origin and differentiation potential are incorporated as adventitial cells in microvessels. Stem Cell Reports, 2016; 6:897–913.
15.
TsaiM-S, HwangS-M, ChenK-D, et al.Functional network analysis of the transcriptomes of mesenchymal stem cells derived from amniotic fluid, amniotic membrane, cord blood, and bone marrow. Stem Cells, 2007; 25:2511–2523.
16.
Roson-BurgoB, Sanchez-GuijoF, Del CañizoC, et al.Transcriptomic portrait of human Mesenchymal Stromal/Stem cells isolated from bone marrow and placenta. BMC Genomics, 2014; 15:910–918.
17.
WieseDM, BraidLR. Transcriptome profiles acquired during cell expansion and licensing validate mesenchymal stromal cell lineage genes. Stem Cell Res Ther, 2020; 11:357.
18.
FleigeS, PfafflMW. RNA integrity and the effect on the real-time qRT-PCR performance. Mol Aspects Med, 2006; 27:126–139.
19.
KönigJ, HuppertzB, DesoyeG, et al.Amnion-derived mesenchymal stromal cells show angiogenic properties but resist differentiation into mature endothelial cells. Stem Cells Dev, 2012; 21:1309–1320.
20.
MartinsJP, SantosJM, de AlmeidaJM, et al.Towards an advanced therapy medicinal product based on mesenchymal stromal cells isolated from the umbilical cord tissue: Quality and safety data. Stem Cell Res Ther, 2014; 5:9–15.
21.
UlrichC, RolauffsB, AbeleH, et al.Low osteogenic differentiation potential of placenta-derived mesenchymal stromal cells correlates with low expression of the transcription factors Runx2 and Twist2. Stem Cells Dev, 2013; 22:2859–2872.
22.
LeekJT, JohnsonWE, ParkerHS, et al.The sva package for removing batch effects and other unwanted variation in high-throughput experiments. Bioinformatics, 2012; 28:882–883.
23.
ZhaoY, WongL, GohWWB. How to do quantile normalization correctly for gene expression data analyses. Sci Rep, 2020; 10:15534.
24.
SubramanianA, TamayoP, MoothaVK, et al.Gene set enrichment analysis: A knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci U S A, 2005; 102:15545–15550.
25.
LiberzonA, BirgerC, ThorvaldsdóttirH, et al.The molecular signatures database hallmark gene set collection. Cell Syst, 2015; 1:417–425.
26.
RitchieME, PhipsonB, WuD, et al.limma powers differential expression analyses for RNA-sequencing and microarray studies. Nucleic Acids Res, 2015; 43:e47.
27.
ChenJ, BardesEE, AronowBJ, et al.ToppGene Suite for gene list enrichment analysis and candidate gene prioritization. Nucleic Acids Res, 2009; 37:W305–W311.
28.
AshburnerM, BallCA, BlakeJA, et al.Gene ontology: Tool for the unification of biology. Nat Genet, 2000; 25:25–29.
29.
ClineMS, SmootM, CeramiE, et al.Integration of biological networks and gene expression data using Cytoscape. Nat Protoc, 2007; 2:2366–2382.
30.
CottenCM, FisherK, MalcolmW, et al.A pilot phase I trial of allogeneic umbilical cord tissue-derived mesenchymal stromal cells in neonates with hypoxic-ischemic encephalopathy. Stem Cells Transl Med, 2023; 12:355–364.
31.
SunJM, DawsonG, FranzL, et al.Infusion of human umbilical cord tissue mesenchymal stromal cells in children with autism spectrum disorder. Stem Cells Transl Med, 2020; 9:1137–1146.
32.
SunJM, CaseLE, McLaughlinC, et al.Motor function and safety after allogeneic cord blood and cord tissue-derived mesenchymal stromal cells in cerebral palsy: An open-label, randomized trial. Dev Med Child Neurol, 2022; 64:1477–1486.
33.
JiangE, QianK, WangL, et al.Efficacy and safety of human umbilical cord-derived mesenchymal stem cells versus placebo added to second-line therapy in patients with steroid-refractory acute graft-versus-host disease: A multicentre, randomized, double-blind, phase 2 trial. BMC Med, 2024; 22:555–514.
34.
CoutoPS, ShatirishviliG, BersenevA, et al.First decade of clinical trials and published studies with mesenchymal stromal cells from umbilical cord tissue. Regen Med, 2019; 14:309–319.
35.
LiuQ-W, HuangQ-M, WuH-Y, et al.Characteristics and therapeutic potential of human amnion-derived stem cells. Int J Mol Sci, 2021; 22:970.
36.
PhinneyDG, KopenG, RighterW, et al.Donor variation in the growth properties and osteogenic potential of human marrow stromal cells. J Cell Biochem, 1999; 75:424–436.
37.
SiegelG, KlubaT, Hermanutz-KleinU, et al.Phenotype, donor age and gender affect function of human bone marrow-derived mesenchymal stromal cells. BMC Med, 2013; 11:146–120.
38.
PaladinoFV, SardinhaLR, PiccinatoCA, et al.Intrinsic variability present in Wharton’s jelly mesenchymal stem cells and T cell responses may impact cell therapy. Stem Cells Int, 2017; 2017:e8492797–e12.
39.
HartML, RuschE, KauppM, et al.Expression of desmoglein 2, desmocollin 3 and plakophilin 2 in placenta and bone marrow-derived mesenchymal stromal cells. Stem Cell Rev Rep, 2017; 13:258–266.
40.
BárciaRN, SantosJM, FilipeM, et al.What makes umbilical cord tissue-derived mesenchymal stromal cells superior immunomodulators when compared to bone marrow derived mesenchymal stromal cells? Stem Cells Int, 2015; 2015:e583984.
MenardC, PacelliL, BassiG, et al.Clinical-grade mesenchymal stromal cells produced under various good manufacturing practice processes differ in their immunomodulatory properties: Standardization of immune quality controls. Stem Cells Dev, 2013; 22:1789–1801.
43.
StubbendorffM, DeuseT, HuaX, et al.Immunological properties of extraembryonic human mesenchymal stromal cells derived from gestational tissue. Stem Cells Dev, 2013; 22:2619–2629.
44.
WegmeyerH, BröskeA-M, LeddinM, et al.Mesenchymal stromal cell characteristics vary depending on their origin. Stem Cells Dev, 2013; 22:2606–2618.
45.
MénardC, DulongJ, RouloisD, et al.Integrated transcriptomic, phenotypic, and functional study reveals tissue-specific immune properties of mesenchymal stromal cells. Stem Cells, 2020; 38:146–159.
46.
BakshD, YaoR, TuanRS. Comparison of proliferative and multilineage differentiation potential of human mesenchymal stem cells derived from umbilical cord and bone marrow. Stem Cells, 2007; 25:1384–1392.
47.
ChenMY, LiePC, LiZL, et al.Endothelial differentiation of Wharton’s jelly–derived mesenchymal stem cells in comparison with bone marrow–derived mesenchymal stem cells. Exp Hematol, 2009; 37:629–640.
48.
WuLF, WangNN, LiuYS, et al.Differentiation of Wharton’s jelly primitive stromal cells into insulin-producing cells in comparison with bone marrow mesenchymal stem cells. Tissue Eng Part A, 2009; 15:2865–2873.
49.
DeuseT, StubbendorffM, Tang-QuanK, et al.Immunogenicity and immunomodulatory properties of umbilical cord lining mesenchymal stem cells. Cell Transplant, 2011; 20:655–667.
50.
In ‘t AnkerPS, ScherjonSA, Kleijburg-van der KeurC, et al.Isolation of mesenchymal stem cells of fetal or maternal origin from human placenta. Stem Cells, 2004; 22:1338–1345.
51.
BarlowS, BrookeG, ChatterjeeK, et al.Comparison of human placenta- and bone marrow-derived multipotent mesenchymal stem cells. Stem Cells Dev, 2008; 17:1095–1107.
52.
BatsaliAK, PontikoglouC, KoutroulakisD, et al.Differential expression of cell cycle and WNT pathway-related genes accounts for differences in the growth and differentiation potential of Wharton’s jelly and bone marrow-derived mesenchymal stem cells. Stem Cell Res Ther, 2017; 8:102–117.
53.
NajiA, EitokuM, FavierB, et al.Biological functions of mesenchymal stem cells and clinical implications. Cell Mol Life Sci, 2019; 76:3323–3348.
54.
KwonA, KimY, KimM, et al.Tissue-specific differentiation potency of mesenchymal stromal cells from perinatal tissues. Sci Rep, 2016; 6:23544.
55.
UngererC, Quade-LyssyP, RadekeHH, et al.Galectin-9 is a suppressor of T and B cells and predicts the immune modulatory potential of mesenchymal stromal cell preparations. Stem Cells Dev, 2014; 23:755–766.
56.
WangD, FengX, LuL, et al.A CD8 T cell/indoleamine 2,3‐Dioxygenase axis is required for mesenchymal stem cell suppression of human systemic lupus erythematosus. Arthritis Rheumatol, 2014; 66:2234–2245.
OmatsuY, SeikeM, SugiyamaT, et al.Foxc1 is a critical regulator of haematopoietic stem/progenitor cell niche formation. Nature, 2014; 508:536–540.
59.
AbdelhakS, KalatzisV, HeiligR, et al.A human homologue of the Drosophila eyes absent gene underlies Branchio-Oto-Renal (BOR) syndrome and identifies a novel gene family. Nat Genet, 1997; 15:157–164.
60.
LiX, OghiKA, ZhangJ, et al.Eya protein phosphatase activity regulates Six1–Dach–Eya transcriptional effects in mammalian organogenesis. Nature, 2003; 426:247–254.
61.
BlevinsMA, TowersCG, PatrickAN, et al.The SIX1-EYA transcriptional complex as a therapeutic target in cancer. Expert Opin Ther Targets, 2015; 19:213–225.
62.
HeanueTA, ReshefR, DavisRJ, et al.Synergistic regulation of vertebrate muscle development by Dach2, Eya2, and Six1, homologs of genes required for Drosophila eye formation. Genes Dev, 1999; 13:3231–3243.
63.
PalmaLG, KarthaGM, MaquedaM, et al.An unbiased genomewide screen uncovers 7 genes that drive hematopoietic stem cell fate from mouse embryonic stem cells. Blood, 2025; 146:328–340.
64.
DongB, ZhuJ, ChenX, et al.The emerging role of Interleukin-(IL)-11/IL-11R in bone metabolism and homeostasis: From cytokine to osteokine. Aging Dis, 2023; 14:2113–2126.
65.
GaoY, ChiY, ChenY, et al.Multi-omics analysis of human mesenchymal stem cells shows cell aging that alters immunomodulatory activity through the downregulation of PD-L1. Nat Commun, 2023; 14:4373.
Supplementary Material
Please find the following supplemental material available below.
For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.
For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.
