cells Review Perinatal Mesenchymal Stromal Cells and Their Possible Contribution to Fetal-Maternal Tolerance Marta Magatti 1, Francesca Romana Stefani 1 , Andrea Papait 1, Anna Cargnoni 1, Alice Masserdotti 2, Antonietta Rosa Silini 1 and Ornella Parolini 1,2,* 1 Centro di Ricerca E. Menni, Fondazione Poliambulanza Istituto Ospedaliero, 25124 Brescia, Italy; [email protected] (M.M.); [email protected] (F.R.S.); [email protected] (A.P.); [email protected] (A.C.); [email protected] (A.R.S.) 2 Istituto di Anatomia Umana e Biologia Cellulare, Università Cattolica del Sacro Cuore, 00168 Roma, Italy; [email protected] * Correspondence: [email protected]; Tel.: +39-0630154464 Received: 27 September 2019; Accepted: 3 November 2019; Published: 7 November 2019 Abstract: During pregnancy, a successful coexistence between the mother and the semi-allogenic fetus occurs which requires a dynamic immune system to guarantee an efficient immune protection against possible infections and tolerance toward fetal antigens. The mechanism of fetal-maternal tolerance is still an open question. There is growing in vitro and in vivo evidence that mesenchymal stromal cells (MSC) which are present in perinatal tissues have a prominent role in generating a functional microenvironment critical to a successful pregnancy. This review highlights the immunomodulatory properties of perinatal MSC and their impact on the major immune cell subsets present in the uterus during pregnancy, such as natural killer cells, antigen-presenting cells (macrophages and dendritic cells), and T cells. Here, we discuss the current understanding and the possible contribution of perinatal MSC in the establishment of fetal-maternal tolerance, providing a new perspective on the physiology of gestation. Keywords: mesenchymal stromal cells; placenta; fetal-maternal tolerance; immunomodulation; pregnancy 1. Immunology of Pregnancy In nature, pregnancy is a unique physiological phenomenon in which the mother coexists with the semi-allogeneic fetus that carries a combination of antigens half of which are paternal. For many years, Medawar’s paradox has provided the basis for the model that explains the cohabitation of mother and fetus [1]. Medawar proposed that the lack of fetal rejection by the mother might be explained by diverse mechanisms, which include: (a) the non-immunogenicity of the fetus due to antigenic immaturity, (b) the suppression of the mother’s immune system during pregnancy that in turn causes the mother’s immune system to “ignore” the fetus, (c) the uterus as an immunologically privileged site; and (d) the existence of an immunological barrier between mother and fetus, represented by the placenta [2]. Since the time of Medawar, the following has been demonstrated: (a) the fetus has immunogenic properties; (b) the maternal immune response is not suppressed during pregnancy; (c) the uterus does not represent an immune-privileged site and extrauterine pregnancies are also possible [3,4]; and (d) there are no physical barriers from immune cells in the placenta, and this is particularly true considering the human hemochorial placental arrangement [5], therefore, allowing bidirectional cell trafficking between the fetus and the mother [6]. Thus, placental tissue represents an active immunological site rather than a merely passive barrier from the mother. There is a great deal of evidence suggesting that a successful Cells 2019, 8, 1401; doi:10.3390/cells8111401 www.mdpi.com/journal/cells Cells 2019, 8, 1401 2 of 22 Cells 2018, 7, x FOR PEER REVIEW 2 of 23 pregnancyis a great requires deal of evidence a responsive suggesting and dynamic that a successful immune pregnancy system from requires both thea responsive mother and and the dynamic fetal and placentalimmune compartments system from both in order the mother to guarantee and the fetal efficient and placental immune protectioncompartments against in order possible to guarantee infections andefficient tolerance immune toward protection fetal antigens. against possible In line with infections the idea and of tolerance a plastic toward immune fetal remodeling, antigens. In distinctline immunologicalwith the idea of stages a plastic are immune identified remodeling, during pregnancy, distinct immunological as previously stages extensively are identified described during [7 ,8] (Figurepregnancy,1). At first,as previously a local proinflammatory extensively described reaction [7,8] accompanies (Figure 1). At the first, adhesion a local andproinflammatory invasion of the trophoblastreaction accompanies to maternal the tissues. adhesion Indeed, and invasion at the beginning of the trophoblast of pregnancy, to maternal the maternaltissues. Indeed, endometrium at the undergoesbeginning a processof pregnancy, called decidualization, the maternal endometrium characterized undergoes by proliferation a process and called differentiation decidualization, of stromal cells.characterized The stromal by cells proliferation release cytokines and differentiation and growth of stromal factors (mainlycells. The prolactin stromal cells and release insulin-like cytokines growth factorand binding growth protein-1)factors (mainly that modify prolactin the and extracellular insulin-like matrix growth and factor expose binding adhesion protein-1) molecules that inmodify order to the extracellular matrix and expose adhesion molecules in order to create a receptive create a receptive microenvironment for the attachment of the embryo, which occurs with the migration microenvironment for the attachment of the embryo, which occurs with the migration of fetal of fetal extravillous trophoblast cells to the decidua. Moreover, soon after implantation, the number of extravillous trophoblast cells to the decidua. Moreover, soon after implantation, the number of immune cells dramatically increases in the stroma of the decidua. In particular, the majority of first immune cells dramatically increases in the stroma of the decidua. In particular, the majority of first trimestertrimester human-decidual human-decidual leukocytes leukocytes areare naturalnatural killer killer (NK) (NK) cells, cells, followed followed by by myeloid myeloid cells, cells, T cells, T cells, andand rare rare dendritic dendritic and and B B cells cells [ 9[9–11].–11]. Figure 1. The immune response in placental tissues during fetal development. The first trimester of Figure 1. The immune response in placental tissues during fetal development. The first trimester of pregnancy is associated with a proinflammatory reaction which is necessary for implantation. In this pregnancy is associated with a proinflammatory reaction which is necessary for implantation. In this phase, placental tissues are characterized by a T helper 1 (Th1) proinflammatory environment. phase, placental tissues are characterized by a T helper 1 (Th1) proinflammatory environment. Natural Natural killer (NK) cells are involved in trophoblast invasion and support neoangiogenesis. A mixed killer (NK) cells are involved in trophoblast invasion and support neoangiogenesis. A mixed M1 and M1 and M2 macrophage population mediates a delicate balance for blastocyst implantation and spiral M2 macrophage population mediates a delicate balance for blastocyst implantation and spiral artery artery remodeling. The second trimester is characterized by a Th2, anti-inflammatory remodeling. The second trimester is characterized by a Th2, anti-inflammatory microenvironment microenvironment pivotal to fetal growth. T regulatory (Treg) cells, M2 macrophages, and NK cells pivotalsupport to fetal and growth. promote T regulatorythe survival (Treg) of the cells, fetus. M2 macrophages,As gestation andreaches NK cellsthe third support trimester, and promote an theinflammatory survival of theandfetus. Th1-type As immune gestation state reaches promotes the the third influx trimester, of immune an inflammatorycells into the myometrium and Th1-type immunewhich stateis crucial promotes to foster the labor influx and of delivery. immune cells into the myometrium which is crucial to foster labor and delivery. Between week 13 and week 27, the second trimester of pregnancy takes place. During this phase thereBetween is a shift week from 13 and the weekinitial 27, proinflammatory the second trimester to an ofanti-inflammatory pregnancy takes place.and T Duringhelper 2 this (Th2) phase thereresponse, is a shift aimed from at the preserving initial proinflammatory the fetal-placental to ansystem anti-inflammatory [12]. The tissue and microenvironment T helper 2 (Th2) is response, now aimed at preserving the fetal-placental system [12]. The tissue microenvironment is now enriched with Cells 2019, 8, 1401 3 of 22 M2-likeCells macrophages 2018, 7, x FOR PEER and REVIEW NK cells, whose interaction induces the generation of T regulatory3 of 23 (Treg) cells, keyenriched players with in M2-like sustaining macrophages fetal-maternal and NK tolerance cells, whose [13, 14interaction]. induces the generation of T Finally,regulatory in the(Treg) third cells, trimester, key players the in return sustaining to an fetal-maternal inflammatory tolerance and Th1-type [13,14]. immune state fosters labor andFinally, delivery. in the In third this trimester, phase, infiltration the return to of an immune inflammatory cells and into Th1-type the myometrium immune state is fosters crucial for promotinglabor and the contractiondelivery. In this of the phase, uterus, infiltration the delivery of immune of