Mesenchymal stromal cells (MSCs) are a heterogeneous population of cells with secretory, immunomodulatory, and homing properties (Viswanathan et al., 2019). This population encompasses fibroblasts, myofibroblasts, pericytes, and tissue-specific progenitor populations. Traditionally researchers defined in vitro expanded MSCs by (1) plastic adherence, (2) expression of CD73, CD90, and CD105, lack of hematopoietic and endothelial marker expression (CD31, CD34, CD45, HLA-DR), and (3) the capacity to differentiate into adipocyte, chondrocyte and osteoblast lineages in vitro (Dominici et al., 2006). However, despite MSCs from different tissue sources (i.e. bone-marrow, adipose, umbilical cord, placenta) sharing expression of the minimal criteria antigens after in vitro culture, they functionally differ in a tissue-specific manner (Du et al., 2016b; Kozlowska et al., 2019). This has been more recently acknowledged in a refined ISCT position statement that requires the tissue origin of MSCs to be provided along with evidence for their in vitro and in vivo functionality (Viswanathan et al., 2019).

It has become clear that in vitro culture may have significant impact on MSC phenotype, meaning that cultured MSCs may have a different phenotype from their in vivo/freshly isolated counterparts. For example, prior to culture adipose-derived MSCs are CD34+, whilst in vitro culture induces the loss of CD34 expression (Lin et al., 2012). The MSC-associated marker CD271 is also lost with plastic culture (Brooks et al., 2020), and MSC αSMA expression can be heavily impacted by culture media (Boss et al., 2020). Thus, the culture conditions used to expand MSCs can mask their true in vivo phenotype and heterogeneity. Furthermore, in any set of culture conditions the most competitive stromal cells will thrive and take over the culture, whilst other functionally diverse cells may be diluted out or lost. Understanding the true in vivo phenotype, and optimising culture conditions to minimize phenotypic ‘drift’ in vitro may enable researchers to better take advantage of the tissue specific properties of MSCs, and enable more accurate study of their roles in vivo.

Placental MSCs (pMSCs) are routinely isolated from the core of placental villi and propagated in culture (Abumaree et al., 2013; Castrechini et al., 2010; Kusuma et al., 2018). The placenta is a highly vascularised organ that develops rapidly over gestation in order to act as the conduit for nutrient and gas exchange between mother and fetus. pMSCs have been reported to reside in a perivascular niche where they can influence vascular development and function (Castrechini et al., 2010). In line with this, cultured pMSCs have well established angiogenic and haematopoietic paracrine effects in vitro and in vivo (Chen et al., 2009; Du et al., 2016a). pMSCs are typically isolated by gross tissue culture methods (explant outgrowths or enzymatic digestion followed by plastic adherence), rather than by expression of specific cell surface markers (Abumaree et al., 2013; Pelekanos et al., 2016). However, using gross digestion techniques it is impossible to determine the niche in which pMSCs reside. Previous work has assumed that in vitro pMSC expression of CD146, a marker with established perivascular expression in vivo, provides evidence of perivascular origins (Castrechini et al., 2010). However, work with bone marrow MSCs suggest CD146 expression is a tissue culture artefact (Blocki et al., 2013), and chipcytometry has localised in vitro MSC markers CD73, CD105 and CD90 outside of the perivascular niche in term placentae (Consentius et al., 2018). Together this sheds doubt on the perivascular origins of pMSCs, and highlights the need to better characterise their ex vivo phenotype in order to understand their functional role in vivo.

Our understanding of mesenchymal heterogeneity is expanding exponentially, and advances in single-cell technologies have uncovered a wide spectrum of mesenchymal and endothelial phenotypes with specific functions and spatial distributions (Suryawanshi et al., 2018; Takeda et al., 2019; Vijay et al., 2019). Mesenchymal heterogeneity can be used to spatially localise cells, identify cells involved in morphogenesis, angiogenesis or quiescence, and characterise inflammatory, anti-inflammatory, or invasive phenotypes (Cimini and Kishore, 2021; Mezawa et al., 2019; Mezheyeuski et al., 2020; Nazari et al., 2016; Quintanilla et al., 2019). Dramatic advances in flow cytometry over the past few decades have enabled the simultaneous quantification of upwards of 30 antigens, allowing detection of in depth cell heterogeneity. Whilst initiated in the haematopoietic field, the wealth of data produced using multicolour flow cytometry has driven the use of this technique for analysis of other cell types, including the mesenchymal lineages. To date the largest panel used to assess mesenchymal cells (16-colours) was designed for analysis with conventional flow cytometry (Brooks et al., 2020). However, spectral flow cytometry has significant potential to further improve analysis of mesenchymal cells. The ability of spectral flow cytometry to measure a larger portion of the spectral signature of each fluorophore, and thus enable small differences between fluorophores to be discriminated, combined with the ability to remove autofluorescence (a prominent feature of mesenchymal cells) paves the way for assessing cells previously regarded as challenging for multicolour flow cytometry.

Here, we developed what to our knowledge is the largest multicolour spectral flow cytometry panel employed to date, in order to characterise the mesenchymal heterogeneity in first trimester placental tissue, and to ascertain the impact of in vitro MSC culture conditions on the subsequent phenotype of these populations.

Common sources of MSCs used in clinical trials include; uncharacterised adipose, bone-marrow, and placental stroma. Identifying functionally different mesenchymal cells and defining the origins for tissue-specific MSCs could improve these applications. Here, we used a high-dimensional flow cytometry panel to uncover at least four different mesenchymal populations with distinct expression profiles in the villous core of first trimester placentae, indicating the presence of functionally specialised cells. This mesenchymal heterogeneity could translate to different physiological capabilities important for clinical therapies and aid understanding of the role of these cells in vivo.

Characterising the villous core populations allows us to better understand how the placenta functions and develops, and enables targeting of populations for functional analysis. From the four mesenchymal populations classified in this work three populations, perivascular cells (Subset Three), podoplanin⁺CD36⁺ cells (Subset Four), and CD26⁺CD90⁺ myofibroblasts (Subset Five) all closely aligned with populations described in prior single-cell RNA sequencing data from first trimester placentae (Suryawanshi et al., 2018). However, this single-cell RNA sequencing dataset did not report a population that aligned with CD73⁺CD90⁺ cells (Subset Two), instead reporting that only endothelial cells expressed CD73 in the placental core. The ability to assess larger cell numbers by flow cytometry in our work, and the low abundance of CD73⁺CD90⁺ cells after 9 weeks of gestation, means that this population may not have been detected as a distinct population by single cell RNA-seq. Furthermore, RNA expression does not always accurately reflect protein expression (Reimegård et al., 2021). This highlights the importance of protein level characterisation of cells from fresh tissue, and the ability of multicolour flow cytometry to undertake this at single cell resolution complements and builds on single cell gene expression datasets.

The first major aspect of this work to consider is what each subset could represent and what its phenotype reflects. CD73⁺CD90⁺ cells were unique from the other mesenchymal populations and could be identified by their expression of CD73, which was shared only with endothelial cells. The abundance of this population at <10 weeks of gestation hints at their involvement in processes that occur early in gestation such as vasculogenesis or haematopoiesis. CD73⁺CD90⁺ cells co-expressed podoplanin, but were distinct from other mesenchymal subsets in that they did not express CD26. This combined expression pattern alludes to two potential functional roles of these cells in the placenta. First, expression of podoplanin and low expression of CD26 are both associated with a migratory/invasive phenotype (Mezawa et al., 2019; Ward et al., 2019). As the decline in abundance of these cells after 9 weeks of gestation corresponds to the regression of villi and blood vessels from the distal side of the gestational sac (Burton and Jauniaux, 2018), this raises the possibility that CD73⁺CD90⁺ cells could be involved in this regression of the villi, or they arise transiently as the result of an early endothelial to mesenchymal transition in the placenta whereby, endothelial cells involved in vascular regression lose their junctional markers and gain a mesenchymal/migratory phenotype (Pinto et al., 2016). Secondly, expression of podoplanin and a lack of CD26 expression on CD73⁺CD90⁺ cells indicates potential roles in haematopoiesis. Several studies have demonstrated that inhibiting CD26 enhances homing, engraftment and differentiation of hematopoietic stem cells (Christopherson et al., 2004; Kawai et al., 2007), and thus a lack of CD26 expression on CD73⁺CD90⁺ cells could suggest they are involved in blood lineage migration/differentiation as both Hofbauer cells (placental macrophages) and nucleated red blood cells are found in the villous stroma in the first trimester (Van Handel et al., 2007). Furthermore, podoplanin identifies connective stroma in lymphoid organs that produces a network of collagen-rich fibres to enable movement of lymphocytes via interactions with leukocyte CLEC-2 receptors (Link et al., 2011; Nazari et al., 2016; Onak Kandemir et al., 2019; Wang et al., 2011). The stroma of early placental villi is poorly vascularised therefore podoplanin⁺ cells could enable blood lineage cells (including Hofbauer cells) to migrate throughout the villous core (Ingman et al., 2010). Indeed, Hofbauer cells have been co-localised with podoplanin expressing stroma in term placentae (Onak Kandemir et al., 2019). Together this suggests CD73⁺CD90⁺ cells may represent a functionally divergent population, that is abundant in the early first trimester placenta which is specialised to facilitate/promote hematopoietic migration and differentiation, and morphogenesis of the placenta during regression of the distal villi.

The largest subset identified, podoplanin⁺CD36⁺ cells (Subset Four) was hypothesised to constitute the majority of connective villous stroma and play an important role in villous stroma expansion. Similar to CD73⁺CD90⁺ cells, the expression of podoplanin in this population suggests they may play a role in facilitating hematopoietic transport throughout the poorly vascularised first trimester stroma, and may have a migratory phenotype. However, podoplanin⁺CD36⁺ cells had a high expression of CD26 which identifies fibroblasts involved in wound healing/fibrosis and the associated extracellular matrix deposition (Soare et al., 2020; Worthen et al., 2020) suggesting an alternative or additional role in villous expansion and growth. The corresponding podoplanin⁺CD36⁺ population observed in the prior single cell RNA-seq dataset, expressed genes associated with angiogenesis (IL6, ANGPTL-4, TNFAIP6), suggesting they may also provide a paracrine stimulus for placental vascular development which is undergoing vasculogenesis and angiogenesis over first trimester (Chang et al., 2012; Hato et al., 2008; Suryawanshi et al., 2018).

Perivascular cells (Subset Three) were identified by their expression of either CD271 or CD146, both markers that localise in a perivascular niche (Castrechini et al., 2010; Lv et al., 2014). CD26⁺CD90⁺ myofibroblasts (Subset Five) were negative for all other markers in Panel One and therefore, were hypothesised to represent contractile/less proliferative myofibroblasts. Indeed, prior single-cell RNA sequencing work identified that populations aligning with perivascular cells and CD26⁺CD90⁺ myofibroblasts reported here had a respectively low or high expression of markers associated with contractile myofibroblasts and mature perivascular cells (ACTA2 (αSMA) and CNN1 (calponin)) (Kumar et al., 2017; Suryawanshi et al., 2018). The lower expression of contractile markers in perivascular cells in comparison to CD26⁺CD90⁺ myofibroblasts may initially appear unexpected, but as the first trimester placental vasculature is relatively immature it would not necessarily be expected that perivascular cells had high expression of contractile markers at this stage of gestation (Zhang et al., 2002). Interestingly, our in vitro experiments demonstrated that both CD73⁺CD90⁺ cells (Subset Two) and podoplanin⁺CD36⁺ cells (Subset Four) upregulated αSMA and calponin when transferred from EGM-2 to advanced-DMEM/F12, paralleling the upregulation observed in explant-isolated first trimester pMSCs when cultured in this medium (Boss et al., 2020). The in vivo niche that CD73⁺CD90⁺ cells and podoplanin⁺CD36⁺ cells reside in could determine whether differentiated cells contribute to perivascular or myofibroblast contractile cells and more specific markers may be required to tease apart these differences. Indeed, in term placentae contractile perivascular cells express both αSMA and calponin, but extravascular αSMA⁺ cells are also present and thought to allow stem villi to contract and expand in volume (Dellschaft et al., 2020; Farley et al., 2004).

Cultured MSCs are often described as homogeneous. However, there is strong evidence that MSCs upregulate/downregulate markers in response to in vitro culture conditions, and underlying functional and phenotypic heterogeneity could be missed (Blocki et al., 2013; Boss et al., 2020; da Silva Meirelles et al., 2015). In the MSC field, CD73 is thought to be ubiquitously expressed by MSCs (Dominici et al., 2006). However, that podoplanin⁺CD36⁺ cells upregulate CD73 expression after culture demonstrates expression of this marker may also be a culture artefact. The phenotypic convergence of different mesenchymal populations was further demonstrated by the loss of CD36 and CD271 expression, from podoplanin⁺CD36⁺ and CD73⁺CD90⁺ cells respectively, additional markers that made these populations distinct ex vivo. However, expression of CD26 was unaffected by culture, and CD146 was differentiability affected by culture in the two populations. This demonstrates that the nuances of culture adaptation are cell-specific as much as they may be media-specific.

Changes to “MSC” phenotype do not necessarily reflect gain/loss in function. For example bone-marrow MSCs isolated by their expression of CD146 stabilize endothelial tube formation in vitro, whereas, CD146^- MSCs, that subsequently upregulate CD146 in vitro, are unable to stablise tube formation (Blocki et al., 2013). Thus, ex vivo phenotype may be a more accurate indicator of a cells’ functional capacity and highlights the importance of characterizing mesenchymal cells prior to culture. The four placental mesenchymal populations identified here are likely to play different roles in the placenta, and therefore have different functional and therapeutic capacities. pMSCs are often acquired by macerating the villous tissue in order to obtain a single cell suspension that is plated in plastic tissue culture flasks (Papait et al., 2020; Pelekanos et al., 2016). Thus all of the populations identified in this work could be present within such single cell suspensions. However, the population/s with a competitive advantage in culture, either as a result of the culture conditions employed, or as a result of the isolation process itself (enzymes involved, explant-based, plated suspension, enriched for expression of a marker), are likely to outcompete and become the dominant cell in culture. Indeed, our group has demonstrated that under different media conditions fetal pMSCs rather than maternal cells are enriched in culture in EGM-2 (Boss et al., 2020). Characterising the explant isolated pMSCs in more depth in this work demonstrated they express podoplanin, CD26, and CD142, making their origins more likely to be podoplanin⁺CD36⁺ (Subset Four) rather than CD73⁺CD90⁺ cells (Subset Two), perivascular cells (Subset Three) or CD26⁺CD90⁺ myofibroblasts (Subset Five). The heterogeneity identified in this work creates an opportunity to select subsets of these mesenchymal cells more suited to specific uses i.e. with anti-inflammatory/immunomodulatory or angiogenic capacity, and to target media conditions that maintain or transform their in vivo phenotype and desired properties. Furthermore, separately culturing these different subsets will allow us to better to understand their functional contributions to placental development, and whether in vitro culture conditions that promote surface marker convergence also result in functional convergence.

Finally, it is important to consider potential limitations of the use of the cell types identified in therapeutic applications, for example the potential pro-coagulant role of cell surface expression of CD142 (Subset Four) (Moll et al., 2020), or the prior association of CD36 expression (seen on Subset Four) with adipose progenitors, raising the possibility that these cells could be prone to differentiating down this pathway in vivo (Gao et al., 2017; Hanschkow et al., 2022). Conversely, the expression of podoplanin (Subset Two and Four), may indicate an increased migratory capacity, which could potentially enhance migration to sites of therapeutic interest when administered in vivo (Ward et al., 2019). Future work to understand the in vivo and ex vivo functional capacity of each subset identified will help elucidate both their role in placental physiology, and inform potential downstream applications of these cells or their counterparts that may be present in term placentae (a more accessible source of placental cells for therapeutic applications).

In conclusion, this work has demonstrated how simplistic post-culture MSC phenotyping will fail to detect the abundant mesenchymal heterogeneity that exists within the placenta. The phenotypic heterogeneity uncovered in first trimester placental mesenchymal cells indicates their potentially diverse functional roles and highlights the crucial need to thoroughly characterise mesenchymal cells that are used in functional assays or in a therapeutic capacity. The success of this multicolour flow cytometry panel in uncovering mesenchymal cell heterogeneity paves the way for other panels assessing mesenchymal and vascularised tissues. Panels like this could be used to assess cellular dysfunction in pathologies such as cancer, cardiovascular disease and infection, as well as to interrogate different tissues in order to better understand cell function. Identifying the pathological phenotype of mesenchymal/vascular cells in pathologies could lead to therapeutic targets. Indeed, in the context of pregnancy, emerging data has suggested that MSC function is altered in the pregnancy complication fetal growth restriction, with potential impacts on placental vascular function (Boss et al., 2021; Gillmore et al., 2022). Thus, this flow cytometry antibody panel, optimised for placental cells, combined with assessment of different stromal subsets identified in this work, could provide an important tool to better understand normal and abnormal placental development and function across gestation.

FCS data files have been provided for flow cytometry presented in Figures 2-3 following the link: http://flowrepository.org/public_experiment_representations/FR-FCM-Z4TJ Figure 4: http://flowrepository.org/public_experiment_representations/FR-FCM-Z4TL Figure 7: http://flowrepository.org/public_experiment_representations/FR-FCM-Z5FV.

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Author details

1. Anna Leabourn Boss

   1. Department of Obstetrics and Gynaecology, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand
   2. School of Biological Sciences, University of Auckland, Auckland, New Zealand

   Contribution

   Conceptualization, Data curation, Formal analysis, Investigation, Visualization, Methodology, Writing - original draft

   For correspondence

   a.boss@auckland.ac.nz

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-1943-4162

2. Tanvi Damani

   School of Biological Sciences, University of Auckland, Auckland, New Zealand

   Contribution

   Investigation

   Competing interests

   No competing interests declared

3. Tayla J Wickman

   Department of Obstetrics and Gynaecology, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand

   Contribution

   Data curation, Formal analysis

   Competing interests

   No competing interests declared

4. Larry W Chamley

   Department of Obstetrics and Gynaecology, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand

   Contribution

   Writing – review and editing

   Competing interests

   No competing interests declared

5. Joanna L James

   Department of Obstetrics and Gynaecology, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand

   Contribution

   Conceptualization, Resources, Supervision, Funding acquisition, Methodology, Project administration, Writing – review and editing

   Contributed equally with

   Anna ES Brooks

   Competing interests

   No competing interests declared

6. Anna ES Brooks

   1. School of Biological Sciences, University of Auckland, Auckland, New Zealand
   2. Maurice Wilkins Centre, University of Auckland, Auckland, New Zealand

   Contribution

   Conceptualization, Resources, Software, Supervision, Funding acquisition, Methodology, Writing – review and editing

   Contributed equally with

   Joanna L James

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0003-3551-6982

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