Editorial Open Access
Copyright ©The Author(s) 2015. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Stem Cells. Jun 26, 2015; 7(5): 789-792
Published online Jun 26, 2015. doi: 10.4252/wjsc.v7.i5.789
Mesenchymal stem cells: A new diagnostic tool?
Maria Teresa Valenti, Antonio Mori, Luca Dalle Carbonare, Department of Medicine, Section of Internal Medicine D, University of Verona, 37134 Verona, Italy
Antonio Mori, Giovanni Malerba, Department of Life and Reproduction Sciences, Section of Biology and Genetics, University of Verona, 37135 Verona, Italy
Author contributions: Valenti MT prepared the original draft; Mori A and Malerba G wrote some sections in the manuscript; Dalle Carbonare L revised the manuscript.
Conflict-of-interest: All authors disclose no financial and personal relationships with other people or organizations that could inappropriately influence (bias) their work.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Maria Teresa Valenti, PhD, Department of Medicine, Section of Internal Medicine D, University of Verona, Piazzale Scuro, 10, 37134 Verona, Italy. mariateresa.valenti@univr.it
Telephone: +39-045-8128450 Fax: +39-045-8027496
Received: January 16, 2015
Peer-review started: January 18, 2015
First decision: March 6, 2015
Revised: March 27, 2015
Accepted: April 28, 2015
Article in press: April 30, 2015
Published online: June 26, 2015

Abstract

Mesenchymal stem cells (MSCs) are progenitor cells capable of self-renewal that can differentiate in multiple tissues and, under specific and standardized culture conditions, expand in vitro with little phenotypic alterations. In recent years, preclinical and clinical studies have focused on MSC analysis and understanding the potential use of these cells as a therapy in a wide range of pathologies, and many applications have been tested. Clinical trials using MSCs have been performed (e.g., for cardiac events, stroke, multiple sclerosis, blood diseases, auto-immune disorders, ischemia, and articular cartilage and bone pathologies), and for many genetic diseases, these cells are considered an important resource. Considering of the biology of MSCs, these cells may also be useful tools for understanding the physiopathology of different diseases, and they can be used to develop specific biomarkers for a broad range of diseases. In this editorial, we discuss the literature related to the use of MSCs for diagnostic applications and we suggest new technologies to improve their employment.

Key Words: Mesenchymal stem cells, Biomarkers, Next generation sequencing, Diagnostic tool, Tumor-initiating cells

Core tip: Mesenchymal stem cells have been considered potential tools for therapeutic applications in a wide range of pathologies. However, these cells may be used to develop specific biomarkers in a broad range of diseases and they could be considered useful tools to perform new strategies to get early diagnoses. Rare stem cell populations can be studied by recent technologies such as Next Generation Sequencing in order to develop specific marker for diagnostic and prognostic applications.



INTRODUCTION

Mesenchymal stem cells (MSCs) reside in many tissues during development, and their differentiation produces specific phenotypes such as osteoblasts, chondrocytes, adipocytes, and myoblasts. In recent years, MSCs have been considered an important source for cell therapy and tissue regeneration in many clinical applications. Tissue damage is followed by an inflammatory response, and pro-inflammatory factors can rescue MSCs and start the repair process. The process of regeneration is quite complex; MSCs interact with stromal and inflammatory cells, and derived factors play an important role in this process[1]. MSCs are also involved in immunosuppression via inhibition of T cells, B cells, dendritic cells and natural killer cells[2-5], and they may exert immunomodulatory activity during the co-transplantation process[1].

In addition to cell therapy, MSCs are also a promising choice for other clinical applications because they can be used as diagnostic tools. The involvement of MSCs in many physiological or physiopathological aspects offers the possibility of targeting these cells, and their related molecular products, circulating in peripheral blood to obtain an early diagnosis by a non-invasive approach.

Diagnostic application of MSCs

In recent years, MSCs have been considered important “biomarkers” for a non-invasive prenatal diagnosis[6]. Accurate prenatal diagnoses without fetal damage are needed to prevent genetic diseases, and MSCs have been identified in fetal blood during the first trimester, albeit at low concentrations. Despite 20 years of research in this area, technical challenges have produced many obstacles to reproducible fetal MSC isolation, and culture strategies have been developed. However, fetal MSCs have been observed in maternal peripheral blood, suggesting that fetal surface antigens could be considered promising biomarkers for a noninvasive prenatal diagnosis[7], and the analysis of neural and MSCs in the amniotic fluid represents a useful tool for the identification of neural tube defects[8].

Recruitment of progenitor cells in the blood stream in response to skeletal damage has been reported[9], and we have shown that circulating MSCs are increased in patients affected by osteoporosis as a consequence of the impairment of osteoblast differentiation[10]. Furthermore, the molecular analyses of genes involved in the differentiation process have revealed an abnormal level of expression of the transcription factor runx2, the master gene of osteogenic differentiation. These data suggest the possibility of using MSC analysis for the evaluation of bone diseases, and the identification of circulating MSCs could be proposed as a noninvasive diagnostic tool.

Circulating stem cells have been observed after ischemic stroke in patients with myocardial infarction[11,12], and this finding suggests that stem cells in the peripheral blood may provide a potential cell marker for prognosis and risk evaluation in patients with cardiac diseases.

Kim et al[13] showed that CD105 MSCs were mobilized in patients with cerebrovascular stroke, and, in particular, the authors demonstrated that the percentage of apoptotic CD105 cells, based on annexin V expression, was higher in patients with cerebral infarcts than that in normal control subjects.

The epithelial mesenchymal transition that occurs during cellular neoplastic transformation makes MSCs an important target for the diagnosis and prognosis of malignant tumors[14]. Because cancer may originate from the neoplastic transformation of progenitors or related early differentiated cells, stem cell-like markers expressed in tumor cells could be of interest for biomarker identification.

New technologies for stem cells

Recent technologies have made possible the study of the molecular biology of cells at different levels (i.e., the genome, epigenome, transcriptome, small RNAome and metabolome). However, the study of stem cells is still a major challenge due to their low numbers and their potency and plasticity. Currently, most stem cell studies reported in the literature apply microarray technology and focus on the gene expression profile analysis of MSCs[7,15-19], cancer stem cells[20-24], tumor-initiating cells[25] and embryonic stem cells. The study of gene expression at the global level is generally a pitfall and an ordeal due to the presence of low expression levels of many genes, which occurs because stem cells need to be ready to undertake a variety of differentiation programs. Accordingly, the study of different individual gene expression profiles is very difficult. Such issues cause the true gene expression signal to be confounded by background noise. At present, more recent Next Generation Sequencing (NGS) technologies[26] are entering the stem cell arena. NGS is based on massive sequencing, and it can be applied for several purposes, such as the detection of transcripts and estimation of their levels (transcriptome), the identification of genome sequence variants (exome, genome) or the examination of modified methylated nucleotides (methylome). It is noteworthy that epigenomic NGS applications[27] can be used to study stem cells because they can be used to investigate gene regulation and genome function during the differentiation and reprogramming processes. Therefore, the Epigenomics Roadmap consortium has been formed by the NIH to create extensive maps of genomic and epigenomic elements in stem cells and ex vivo tissue[28]. NGS methods can be used to sequence single cells (DNA and/or RNA) opening avenues to thoroughly investigate how differential gene expression in individual cells defines cellular differentiation, function and physiology[22], making it possible to study rare stem cell populations and to investigate the prevalence and differences of potential stem cell subpopulations in cancers or other types of tissue[29].

CONCLUSION

Although several molecules such as Stro-1, CD271, SSEA-4 and CD146 are already recognized as markers for MCS cells[30], it would be useful to have even more specific markers for stem cell potential before MSC cells can serve as reliable tools for standardized diagnostic methods. In conclusion, the analysis of MSCs and their related molecular products supported by new sequencing technologies may lead to the identification of potential biomarkers that could represent useful tools for noninvasive or less invasive diagnostic and prognostic applications for a wide range of diseases. In addition, the individualization of specific markers linked to MSCs could be used to develop new strategies to obtain early diagnoses and start therapeutic approaches for patients as soon as possible.

Certainly, further investigations are necessary to validate and improve the sensitivity of specific biomarkers linked to MSCs, and innovative and costly technologies are required considering the low number and plasticity of MSCs.

Footnotes

P- Reviewer: Goebel WS, Ho I, Hwang SM S- Editor: Ji FF L- Editor: A E- Editor: Wang CH

References
1.  Shi Y, Su J, Roberts AI, Shou P, Rabson AB, Ren G. How mesenchymal stem cells interact with tissue immune responses. Trends Immunol. 2012;33:136-143.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 456]  [Cited by in F6Publishing: 430]  [Article Influence: 35.8]  [Reference Citation Analysis (0)]
2.  Jang JE, Hyun SY, Kim YD, Yoon SH, Hwang DY, Kim SJ, Kim Y, Kim JS, Cheong JW, Min YH. Risk factors for progression from cytomegalovirus viremia to cytomegalovirus disease after allogeneic hematopoietic stem cell transplantation. Biol Blood Marrow Transplant. 2012;18:881-886.  [PubMed]  [DOI]  [Cited in This Article: ]
3.  Corcione A, Benvenuto F, Ferretti E, Giunti D, Cappiello V, Cazzanti F, Risso M, Gualandi F, Mancardi GL, Pistoia V. Human mesenchymal stem cells modulate B-cell functions. Blood. 2006;107:367-372.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 1263]  [Cited by in F6Publishing: 1235]  [Article Influence: 65.0]  [Reference Citation Analysis (0)]
4.  Spaggiari GM, Capobianco A, Abdelrazik H, Becchetti F, Mingari MC, Moretta L. Mesenchymal stem cells inhibit natural killer-cell proliferation, cytotoxicity, and cytokine production: role of indoleamine 2,3-dioxygenase and prostaglandin E2. Blood. 2008;111:1327-1333.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 799]  [Cited by in F6Publishing: 787]  [Article Influence: 46.3]  [Reference Citation Analysis (0)]
5.  Chiesa S, Morbelli S, Morando S, Massollo M, Marini C, Bertoni A, Frassoni F, Bartolomé ST, Sambuceti G, Traggiai E. Mesenchymal stem cells impair in vivo T-cell priming by dendritic cells. Proc Natl Acad Sci USA. 2011;108:17384-17389.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 193]  [Cited by in F6Publishing: 207]  [Article Influence: 15.9]  [Reference Citation Analysis (0)]
6.  O’Donoghue K, Choolani M, Chan J, de la Fuente J, Kumar S, Campagnoli C, Bennett PR, Roberts IA, Fisk NM. Identification of fetal mesenchymal stem cells in maternal blood: implications for non-invasive prenatal diagnosis. Mol Hum Reprod. 2003;9:497-502.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 104]  [Cited by in F6Publishing: 108]  [Article Influence: 5.1]  [Reference Citation Analysis (0)]
7.  Weng SL, Chang SJ, Cheng YC, Wang HY, Wang TY, Chang MD, Wang HW. Comparative transcriptome analysis reveals a fetal origin for mesenchymal stem cells and novel fetal surface antigens for noninvasive prenatal diagnosis. Taiwan J Obstet Gynecol. 2011;50:447-457.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 13]  [Cited by in F6Publishing: 14]  [Article Influence: 1.2]  [Reference Citation Analysis (0)]
8.  Pennington EC, Gray FL, Ahmed A, Zurakowski D, Fauza DO. Targeted quantitative amniotic cell profiling: a potential diagnostic tool in the prenatal management of neural tube defects. J Pediatr Surg. 2013;48:1205-1210.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 17]  [Cited by in F6Publishing: 17]  [Article Influence: 1.5]  [Reference Citation Analysis (0)]
9.  Ramírez M, Lucia A, Gómez-Gallego F, Esteve-Lanao J, Pérez-Martínez A, Foster C, Andreu AL, Martin MA, Madero L, Arenas J. Mobilisation of mesenchymal cells into blood in response to skeletal muscle injury. Br J Sports Med. 2006;40:719-722.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 44]  [Cited by in F6Publishing: 47]  [Article Influence: 2.6]  [Reference Citation Analysis (0)]
10.  Dalle Carbonare L, Valenti MT, Zanatta M, Donatelli L, Lo Cascio V. Circulating mesenchymal stem cells with abnormal osteogenic differentiation in patients with osteoporosis. Arthritis Rheum. 2009;60:3356-3365.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 116]  [Cited by in F6Publishing: 120]  [Article Influence: 8.0]  [Reference Citation Analysis (0)]
11.  Paczkowska E, Kucia M, Koziarska D, Halasa M, Safranow K, Masiuk M, Karbicka A, Nowik M, Nowacki P, Ratajczak MZ. Clinical evidence that very small embryonic-like stem cells are mobilized into peripheral blood in patients after stroke. Stroke. 2009;40:1237-1244.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 153]  [Cited by in F6Publishing: 165]  [Article Influence: 11.0]  [Reference Citation Analysis (0)]
12.  Leone AM, Rutella S, Bonanno G, Abbate A, Rebuzzi AG, Giovannini S, Lombardi M, Galiuto L, Liuzzo G, Andreotti F. Mobilization of bone marrow-derived stem cells after myocardial infarction and left ventricular function. Eur Heart J. 2005;26:1196-1204.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 188]  [Cited by in F6Publishing: 196]  [Article Influence: 10.3]  [Reference Citation Analysis (0)]
13.  Kim SJ, Moon GJ, Cho YH, Kang HY, Hyung NK, Kim D, Lee JH, Nam JY, Bang OY. Circulating mesenchymal stem cells microparticles in patients with cerebrovascular disease. PLoS One. 2012;7:e37036.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 36]  [Cited by in F6Publishing: 40]  [Article Influence: 3.3]  [Reference Citation Analysis (0)]
14.  Pirozzi G, Tirino V, Camerlingo R, La Rocca A, Martucci N, Scognamiglio G, Franco R, Cantile M, Normanno N, Rocco G. Prognostic value of cancer stem cells, epithelial-mesenchymal transition and circulating tumor cells in lung cancer. Oncol Rep. 2013;29:1763-1768.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 43]  [Cited by in F6Publishing: 45]  [Article Influence: 4.1]  [Reference Citation Analysis (0)]
15.  Roson-Burgo B, Sanchez-Guijo F, Del Cañizo C, De Las Rivas J. Transcriptomic portrait of human Mesenchymal Stromal/Stem cells isolated from bone marrow and placenta. BMC Genomics. 2014;15:910.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 43]  [Cited by in F6Publishing: 50]  [Article Influence: 5.0]  [Reference Citation Analysis (0)]
16.  Tsai MS, Hwang SM, Chen KD, Lee YS, Hsu LW, Chang YJ, Wang CN, Peng HH, Chang YL, Chao AS. 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.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 165]  [Cited by in F6Publishing: 166]  [Article Influence: 9.8]  [Reference Citation Analysis (0)]
17.  Menicanin D, Bartold PM, Zannettino AC, Gronthos S. Genomic profiling of mesenchymal stem cells. Stem Cell Rev. 2009;5:36-50.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 53]  [Cited by in F6Publishing: 46]  [Article Influence: 3.1]  [Reference Citation Analysis (0)]
18.  Hsieh JY, Wang HW, Chang SJ, Liao KH, Lee IH, Lin WS, Wu CH, Lin WY, Cheng SM. Mesenchymal stem cells from human umbilical cord express preferentially secreted factors related to neuroprotection, neurogenesis, and angiogenesis. PLoS One. 2013;8:e72604.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 195]  [Cited by in F6Publishing: 215]  [Article Influence: 19.5]  [Reference Citation Analysis (0)]
19.  Lis R, Touboul C, Halabi NM, Madduri AS, Querleu D, Mezey J, Malek JA, Suhre K, Rafii A. Mesenchymal cell interaction with ovarian cancer cells induces a background dependent pro-metastatic transcriptomic profile. J Transl Med. 2014;12:59.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 22]  [Cited by in F6Publishing: 25]  [Article Influence: 2.5]  [Reference Citation Analysis (0)]
20.  Beier D, Hau P, Proescholdt M, Lohmeier A, Wischhusen J, Oefner PJ, Aigner L, Brawanski A, Bogdahn U, Beier CP. CD133(+) and CD133(-) glioblastoma-derived cancer stem cells show differential growth characteristics and molecular profiles. Cancer Res. 2007;67:4010-4015.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 850]  [Cited by in F6Publishing: 819]  [Article Influence: 48.2]  [Reference Citation Analysis (0)]
21.  Lottaz C, Beier D, Meyer K, Kumar P, Hermann A, Schwarz J, Junker M, Oefner PJ, Bogdahn U, Wischhusen J. Transcriptional profiles of CD133+ and CD133- glioblastoma-derived cancer stem cell lines suggest different cells of origin. Cancer Res. 2010;70:2030-2040.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 196]  [Cited by in F6Publishing: 187]  [Article Influence: 13.4]  [Reference Citation Analysis (0)]
22.  Merlos-Suárez A, Barriga FM, Jung P, Iglesias M, Céspedes MV, Rossell D, Sevillano M, Hernando-Momblona X, da Silva-Diz V, Muñoz P. The intestinal stem cell signature identifies colorectal cancer stem cells and predicts disease relapse. Cell Stem Cell. 2011;8:511-524.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 666]  [Cited by in F6Publishing: 682]  [Article Influence: 52.5]  [Reference Citation Analysis (0)]
23.  Engström PG, Tommei D, Stricker SH, Ender C, Pollard SM, Bertone P. Digital transcriptome profiling of normal and glioblastoma-derived neural stem cells identifies genes associated with patient survival. Genome Med. 2012;4:76.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 39]  [Cited by in F6Publishing: 43]  [Article Influence: 3.6]  [Reference Citation Analysis (0)]
24.  Schwede M, Spentzos D, Bentink S, Hofmann O, Haibe-Kains B, Harrington D, Quackenbush J, Culhane AC. Stem cell-like gene expression in ovarian cancer predicts type II subtype and prognosis. PLoS One. 2013;8:e57799.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 26]  [Cited by in F6Publishing: 28]  [Article Influence: 2.5]  [Reference Citation Analysis (0)]
25.  Liu JC, Voisin V, Bader GD, Deng T, Pusztai L, Symmans WF, Esteva FJ, Egan SE, Zacksenhaus E. Seventeen-gene signature from enriched Her2/Neu mammary tumor-initiating cells predicts clinical outcome for human HER2+: ERα- breast cancer. Proc Natl Acad Sci USA. 2012;109:5832-5837.  [PubMed]  [DOI]  [Cited in This Article: ]
26.  Metzker ML. Sequencing technologies - the next generation. Nat Rev Genet. 2010;11:31-46.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 4795]  [Cited by in F6Publishing: 3955]  [Article Influence: 263.7]  [Reference Citation Analysis (0)]
27.  Rizzo JM, Buck MJ. Key principles and clinical applications of “next-generation” DNA sequencing. Cancer Prev Res (Phila). 2012;5:887-900.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 145]  [Cited by in F6Publishing: 122]  [Article Influence: 10.2]  [Reference Citation Analysis (0)]
28.  Bernstein BE, Stamatoyannopoulos JA, Costello JF, Ren B, Milosavljevic A, Meissner A, Kellis M, Marra MA, Beaudet AL, Ecker JR. The NIH Roadmap Epigenomics Mapping Consortium. Nat Biotechnol. 2010;28:1045-1048.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 1375]  [Cited by in F6Publishing: 1264]  [Article Influence: 97.2]  [Reference Citation Analysis (0)]
29.  Dalerba P, Kalisky T, Sahoo D, Rajendran PS, Rothenberg ME, Leyrat AA, Sim S, Okamoto J, Johnston DM, Qian D. Single-cell dissection of transcriptional heterogeneity in human colon tumors. Nat Biotechnol. 2011;29:1120-1127.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 569]  [Cited by in F6Publishing: 527]  [Article Influence: 40.5]  [Reference Citation Analysis (0)]
30.  Lv FJ, Tuan RS, Cheung KM, Leung VY. Concise review: the surface markers and identity of human mesenchymal stem cells. Stem Cells. 2014;32:1408-1419.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 644]  [Cited by in F6Publishing: 700]  [Article Influence: 77.8]  [Reference Citation Analysis (0)]