Download PDF
Am J Perinatol 2015; 32(06): 605-614
DOI: 10.1055/s-0035-1547322
Original Article
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Circulating Serum-Derived Microparticles Provide Novel Proteomic Biomarkers of Spontaneous Preterm Birth

Alan M. Ezrin
1   NX Prenatal Inc., Louisville, Kentucky
,
Brian Brohman
2   NX Prenatal Inc., Maternal Fetal Medicine Program, Louisville, Kentucky
,
Jackie Willmot
3   Department of Prenatal Diagnostics, NX Prenatal Inc., Maternal Fetal Medicine Program, Louisville, Kentucky
,
Sarah Baxter
4   David H. Murdock Research Institute, Kannapolis, North Carolina
5   Department of Hematologic Oncology, Levine Cancer Institute, Carolinas Healthcare System, Charlotte, North Carolina
,
Keith Moore
6   Moore BioAnalysis, Blue Bell, Pennsylvania
,
Mike Luther
7   Department of Discovery and Development, AMRI, Burlington, Massachusetts
,
Michael R. Fannon
8   BioIT Solutions Inc., Silver Spring, Maryland
,
Baha Sibai
9   Division of Maternal Fetal Medicine, Department of Obstetrics, Gynecology and Reproductive Sciences, University of Texas Health Science Center at Houston (UTHealth) Medical School, Houston, Texas
› Author Affiliations
Further Information

Publication History

20 August 2014

12 January 2015

Publication Date:
31 March 2015 (online)

    Permissions and Reprints

Abstract

Objective The purpose of this study was to determine whether the proteomic biosignature of circulating microparticles in maternal serum obtained in the second trimester could identify pregnancies that result in spontaneous preterm birth (SPTB).

Study Design Microparticles were isolated from blinded biorepository-sourced serum samples from 48 pregnant women at 15 to 17 weeks of gestation. Microparticle proteins were extracted and analyzed using label-free liquid chromatography/mass spectrometry. Peptide features were analyzed to assess the association of specific protein patterns with subjects delivering at term (≥ 37 weeks gestation; n = 24) and those experiencing SPTB (≤ 34 weeks gestation; n = 24).

Results We found 99 proteins that had statistically significant differences in signal intensity between term and SPTB women in both first (n = 26) and second (n = 22) singleton gestation pregnancy cohorts. Additional evaluation identified 18 biomarkers that met criteria for further priority evaluation (12 preterm, 6 term). Pathway analysis showed that differentiating SPTB biomarker proteins were predominantly associated with inflammation and cell injury, while differentiating term biomarkers were associated with cell growth and hematological parameters.

Conclusion This study shows for the first time that the proteomic content of serum microparticles isolated in the second trimester can identify with a high degree of accuracy pregnancies that result in SPTB.

Keywords

preterm birth risk - molecular diagnostic - circulating microparticle - proteomics - microvesicle - exosome
 

  • References

  • 1 Howson CP, Kinney MV, Lawn JE. March of Dimes, PMNCH, Save the Children, WHO. Born Too Soon: The Global Action Report on Preterm Birth. Geneva: World Health Organization; 2012
    Google Scholar
  • 2 Conde-Agudelo A, Papageorghiou AT, Kennedy SH, Villar J. Novel biomarkers for the prediction of the spontaneous preterm birth phenotype: a systematic review and meta-analysis. BJOG 2011; 118 (9) 1042-1054
    CrossrefPubMedGoogle Scholar
  • 3 Taylor DD, Akyol S, Gercel-Taylor C. Pregnancy-associated exosomes and their modulation of T cell signaling. J Immunol 2006; 176 (3) 1534-1542
    CrossrefPubMedGoogle Scholar
  • 4 Mincheva-Nilsson L, Baranov V. The role of placental exosomes in reproduction. Am J Reprod Immunol 2010; 63 (6) 520-533
    CrossrefPubMedGoogle Scholar
  • 5 Atay S, Gercel-Taylor C, Suttles J, Mor G, Taylor DD. Trophoblast-derived exosomes mediate monocyte recruitment and differentiation. Am J Reprod Immunol 2011; 65 (1) 65-77
    CrossrefPubMedGoogle Scholar
  • 6 Sabapatha A, Gercel-Taylor C, Taylor DD. Specific isolation of placenta-derived exosomes from the circulation of pregnant women and their immunoregulatory consequences. Am J Reprod Immunol 2006; 56 (5-6) 345-355
    CrossrefPubMedGoogle Scholar
  • 7 Gercel-Taylor C, Atay S, Tullis RH, Kesimer M, Taylor DD. Nanoparticle analysis of circulating cell-derived vesicles in ovarian cancer patients. Anal Biochem 2012; 428 (1) 44-53
    CrossrefPubMedGoogle Scholar
  • 8 Dragovic RA, Gardiner C, Brooks AS , et al. Sizing and phenotyping of cellular vesicles using Nanoparticle Tracking Analysis. Nanomedicine (Lond) 2011; 7 (6) 780-788
    CrossrefPubMedGoogle Scholar
  • 9 Beer LA, Tang HY, Sriswasdi S, Barnhart KT, Speicher DW. Systematic discovery of ectopic pregnancy serum biomarkers using 3-D protein profiling coupled with label-free quantitation. J Proteome Res 2011; 10 (3) 1126-1138
    CrossrefPubMedGoogle Scholar
  • 10 Epple LM, Griffiths SG, Dechkovskaia AM , et al. Medulloblastoma exosome proteomics yield functional roles for extracellular vesicles. PLoS ONE 2012; 7 (7) e42064
    CrossrefPubMedGoogle Scholar
  • 11 McLean M, Bisits A, Davies J , et al. Predicting risk of preterm delivery by second-trimester measurement of maternal plasma corticotropin-releasing hormone and alpha-fetoprotein concentrations. Am J Obstet Gynecol 1999; 181 (1) 207-215
    CrossrefPubMedGoogle Scholar
  • 12 Melamed N, Hiersch L, Meizner I, Bardin R, Wiznitzer A, Yogev Y. Is measurement of cervical length an accurate predictive tool in women with a history of preterm delivery who present with threatened preterm labor?. Ultrasound Obstet Gynecol 2014; 44 (6) 661-668
    CrossrefPubMedGoogle Scholar
  • 13 Stella CL, Bennett MR, Devarajan P , et al. Preterm labor biomarker discovery in serum using 3 proteomic profiling methodologies. Am J Obstet Gynecol 2009; 201 (4) 387.e1-387.e13
    CrossrefPubMedGoogle Scholar
  • 14 Olver C, Vidal M. Proteomic analysis of secreted exosomes. Subcell Biochem 2007; 43: 99-131
    PubMedGoogle Scholar
  • 15 Simpson RJ, Jensen SS, Lim JW. Proteomic profiling of exosomes: current perspectives. Proteomics 2008; 8 (19) 4083-4099
    CrossrefPubMedGoogle Scholar
  • 16 Pant S, Hilton H, Burczynski ME. The multifaceted exosome: biogenesis, role in normal and aberrant cellular function, and frontiers for pharmacological and biomarker opportunities. Biochem Pharmacol 2012; 83 (11) 1484-1494
    CrossrefPubMedGoogle Scholar
  • 17 Théry C. Exosomes: secreted vesicles and intercellular communications. F1000 Biol Rep 2011; 3: 15
    PubMedGoogle Scholar
  • 18 Esplin MS, Merrell K, Goldenberg R , et al; Eunice Kennedy Shriver National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network. Proteomic identification of serum peptides predicting subsequent spontaneous preterm birth. Am J Obstet Gynecol 2011; 204 (5) 391.e1-391.e8
    CrossrefPubMedGoogle Scholar
  • 19 Saunders RD, Nakajima ST, Rai SN, Pan J, Gercel-Taylor C, Taylor DD. Alterations in antibody subclass immune reactivity to trophoblast-derived fetal fibronectin and α2-macroglobulin in women with recurrent pregnancy loss. Am J Reprod Immunol 2012; 68 (5) 438-449
    CrossrefPubMedGoogle Scholar
  • 20 Christiaens I, Zaragoza DB, Guilbert L, Robertson SA, Mitchell BF, Olson DM. Inflammatory processes in preterm and term parturition. J Reprod Immunol 2008; 79 (1) 50-57
    CrossrefPubMedGoogle Scholar
  • 21 Lindström TM, Bennett PR. The role of nuclear factor kappa B in human labour. Reproduction 2005; 130 (5) 569-581
    CrossrefPubMedGoogle Scholar
  • 22 Hadfield KA, McCracken SA, Ashton AW, Nguyen TG, Morris JM. Regulated suppression of NF-κB throughout pregnancy maintains a favourable cytokine environment necessary for pregnancy success. J Reprod Immunol 2011; 89 (1) 1-9
    CrossrefPubMedGoogle Scholar
  • 23 MacIntyre DA, Sykes L, Teoh TG, Bennett PR. Prevention of preterm labour via the modulation of inflammatory pathways. J Matern Fetal Neonatal Med 2012; 25 (Suppl. 01) 17-20
    CrossrefPubMedGoogle Scholar
  • 24 Lee Y, Sooranna SR, Terzidou V , et al. Interactions between inflammatory signals and the progesterone receptor in regulating gene expression in pregnant human uterine myocytes. J Cell Mol Med 2012; 16 (10) 2487-2503
    CrossrefPubMedGoogle Scholar
  • 25 Tang HY, Beer LA, Barnhart KT, Speicher DW. Rapid verification of candidate serological biomarkers using gel-based, label-free multiple reaction monitoring. J Proteome Res 2011; 10 (9) 4005-4017
    CrossrefPubMedGoogle Scholar
  • 26 Regnier FE, Skates SJ, Mesri M , et al. Protein-based multiplex assays: mock presubmissions to the US Food and Drug Administration. Clin Chem 2010; 56 (2) 165-171
    CrossrefPubMedGoogle Scholar