International Journal of Molecular Sciences Review Exosomes as Biomarkers for Female Reproductive Diseases Diagnosis and Therapy Sahar Esfandyari 1,2,†, Hoda Elkafas 1,3,† , Rishi Man Chugh 1,4, Hang-soo Park 5 , Antonia Navarro 5 and Ayman Al-Hendy 5,* 1 Department of Surgery, University of Illinois at Chicago, Chicago, IL 60612, USA; [email protected] (S.E.); [email protected] (H.E.); [email protected] (R.M.C.) 2 Department of Physiology and Biophysics, University of Illinois at Chicago, Chicago, IL 60612, USA 3 Department of Pharmacology and Toxicology, Egyptian Drug Authority (EDA) Formally, (NODCAR), Cairo 35521, Egypt 4 Department of Radiation Oncology, University of Kansas Medical Center, Kansas City, KS 66160, USA 5 Department of Obstetrics and Gynecology, University of Chicago, Chicago, IL 60637, USA; [email protected] (H.-s.P.); [email protected] (A.N.) * Correspondence: [email protected]; Tel.: +1-773-832-0742 † These authors equally contributed in this work. Abstract: Cell–cell communication is an essential mechanism for the maintenance and development of various organs, including the female reproductive system. Today, it is well-known that the function of the female reproductive system and successful pregnancy are related to appropriate follicular growth, oogenesis, implantation, embryo development, and proper fertilization, dependent on the main regulators of cellular crosstalk, exosomes. During exosome synthesis, selective packaging of different factors into these vesicles happens within the originating cells. Therefore, exosomes Citation: Esfandyari, S.; Elkafas, H.; contain both genetic and proteomic data that could be applied as biomarkers or therapeutic targets Chugh, R.M.; Park, H.-s.; Navarro, A.; in pregnancy-associated disorders or placental functions. In this context, the present review aims to Al-Hendy, A. Exosomes as compile information about the potential exosomes with key molecular cargos that are dysregulated in Biomarkers for Female Reproductive female reproductive diseases which lead to infertility, including polycystic ovary syndrome (PCOS), Diseases Diagnosis and Therapy. Int. premature ovarian failure (POF), Asherman syndrome, endometriosis, endometrial cancer, cervical J. Mol. Sci. 2021, 22, 2165. https:// cancer, ovarian cancer, and preeclampsia, as well as signaling pathways related to the regulation of doi.org/10.3390/ijms22042165 the reproductive system and pregnancy outcome during these pathological conditions. This review might help us realize the etiology of reproductive dysfunction and improve the early diagnosis and Academic Editor: Rosalia C.M. Simmen treatment of the related complications. Received: 22 January 2021 Keywords: Exosome; infertility; female reproductive diseases Accepted: 18 February 2021 Published: 22 February 2021 Publisher’s Note: MDPI stays neutral 1. Introduction with regard to jurisdictional claims in Intercellular interaction is a critical factor in organizing cellular events in all organisms. published maps and institutional affil- In multicellular organisms, various strategies have been implied in cellular cross-talk and iations. cell–cell communication. These strategies are either direct interplay by gap junctions or an indirect mechanism in which secreted extracellular signals are involved [1]. The second procedure follows different stages, such as the production and secretion of hormones, cytokines, and growth factors into the extracellular spaces and their attachment to the target Copyright: © 2021 by the authors. cells for influencing target cells’ activities. The transmission of hormones in the circulation Licensee MDPI, Basel, Switzerland. system is the most prominent example of intercellular interaction resulting in specific This article is an open access article signaling pathways among cells [2]. Mainly, cells in the reproductive tissues are in constant distributed under the terms and communication affected by autocrine (the same cell generating the signal), endocrine conditions of the Creative Commons (between distant cells), and paracrine (between nearby cells) signaling pathways [3,4]. Attribution (CC BY) license (https:// Several studies have recently suggested extracellular vesicles (EVs) as a new mech- creativecommons.org/licenses/by/ anism mediating cellular crosstalk within or among tissues [5–7]. Moreover, the use of 4.0/). Int. J. Mol. Sci. 2021, 22, 2165. https://doi.org/10.3390/ijms22042165 https://www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2021, 22, x FOR PEER REVIEW 2 of 26 Int. J. Mol. Sci. 2021, 22, 2165 Several studies have recently suggested extracellular vesicles (EVs) as a new mecha-2 of 26 nism mediating cellular crosstalk within or among tissues [5–7]. Moreover, the use of EVs in diagnosis and treatment has been indicated in many studies. EVs are an interesting subjectEVs in in diagnosis reproductive and treatment disorder has therapeutics been indicated because in many of their studies. ability EVs to aretransfer an interesting various moleculessubject in either reproductive in normal disorder or abnormal therapeutics conditions because [8]. EVs of their are abilitya heterogeneous to transfer popula- various tionmolecules of nanoparticles either in normal secreted or abnormal by different conditions cells in [ 8an]. EVsevolutionarily are a heterogeneous conserved population manner [9,10].of nanoparticles This shuttling secreted activity by happens different throug cells inh anat evolutionarilyleast two mechanisms: conserved (i) mannerby the recep- [9,10]. tor/ligandThis shuttling interaction activity between happens EVs through and target at least cells two or mechanisms: (ii) by attachment (i) by the of EVs receptor/ligand with target plasmainteraction cells between following EVs the and membrane/membrane target cells or (ii) by attachment fusion with of the EVs transfer with target of their plasma content cells withinfollowing the target the membrane/membrane cells [8,11,12]. Therefore, fusion these with vesicles the transfer contain of bioactive their content molecular within sig- the nals,target including cells [8,11 DNAs,,12]. Therefore, RNAs (b theseoth coding vesicles and contain non-coding bioactive RN molecularAs), lipids, signals, and proteins, including asDNAs, well as RNAs chemical (both compounds coding and non-codinglike drugs, RNAs),including lipids, Cisplatin, and proteins, Doxorubicin, as well Curcumin, as chemical andcompounds Acridine likeOrange, drugs, which including mediate Cisplatin, target Doxorubicin,cells’ functions Curcumin, by either andinduction Acridine of surface Orange, ligandswhich mediateor transferring target cells’ factors functions associated by either with induction different of biological surface ligands pathways or transferring [9,13,14]. Nevertheless,factors associated the EVs with role different in cell–cell biological communication pathways [9 ,13is ,highly14]. Nevertheless, influenced by the the EVs micro- role in environmentcell–cell communication they are present is highly in, for influenced example, by the the pH. microenvironment In this case, it was they reported are present that in, therefor example, was a higher the pH. release In this and case, uptake it was of reported EVs at lower that there pH in was contrast a higher to releasea buffered and condi- uptake tionof EVs [11,15]. at lower Furthermore, pH in contrast along to with a buffered the rapid condition growth [ 11of, 15epigenetic]. Furthermore, investigations, along with there the israpid great growth evidence of epigenetic that circulating investigations, EVs might there transfer is great information evidence that as foreign circulating genes EVs to might ger- minaltransfer cells. information In other words, as foreign it was genes indicated to germinal that somatic cells. nucleic In other acids words, were it transferred was indicated to germinalthat somatic cells nucleic by EVs, acids which were subsequently transferred toacted germinal as the cells final by recipients EVs, which of subsequentlysomatic cell- derivedacted as data the final[16]. recipients of somatic cell-derived data [16]. ThereThere are are different different types types of ofEVs, EVs, includin includingg exosomes, exosomes, microvesic microvesiclesles (MVs), (MVs), apoptotic apop- bodiestotic bodies (ABs) (ABs)according according to their to theirsize, size,specif specificic surface surface markers, markers, biogenesis, biogenesis, and andcontent con- [17,18].tent [17 Among,18]. Among them, them, exosomes exosomes are areknown known as aseffective effective paracrine paracrine regulators regulators of of cellular cellular crosstalkcrosstalk and and are are present present in in various various biological biological fluids. fluids. Different Different functions functions have have been been iden- iden- tifiedtified for for these these molecules, molecules, including including metabolism metabolism regulation, regulation, cell cell proliferation, proliferation, apoptosis, apoptosis, angiogenesis,angiogenesis, antigen antigen presenting, presenting, inflammatory inflammatory pathways, pathways, tumor tumor pathogenesis, pathogenesis, tissue tissue re- pair,repair, and and reproduction reproduction [19–21]. [19–21 ]. Exosome secretion has been addressed in a variety of reproductive cells, such as Exosome secretion has been addressed in a variety of reproductive cells, such as en- endometrial cells [22], follicular cells [5], embryos produced in vitro [23], and oviductal dometrial cells [22], follicular cells [5], embryos produced