The placenta is crucial for a successful pregnancy and the health of both the fetus and the pregnant woman. However, how the human trophoblast lineage is regulated, including the categorization of the placental cell subtypes is poorly understood. Here we performed single-cell RNA sequencing (RNA-seq) on sorted placental cells from first- and second-trimester human placentas. New subtypes of cells of the known cytotrophoblast cells (CTBs), extravillous trophoblast cells (EVTs), Hofbauer cells, and mesenchymal stromal cells were identified and cell-type-specific gene signatures were defined. Functionally, this study revealed many previously unknown functions of the human placenta. Notably, 102 polypeptide hormone genes were found to be expressed by various subtypes of placental cells, which suggests a complex and significant role of these hormones in regulating fetal growth and adaptations of maternal physiology to pregnancy. These results document human placental trophoblast differentiation at single-cell resolution and thus advance our understanding of human placentation during the early stage of pregnancy.

/pdf/single-cell-rna-seq-reveals-the-diversity-of-trophoblast-31j4pj0570.pdf

Single-cell RNA-seq reveals the diversity of trophoblast subtypes and patterns of differentiation in the human placenta

Mesenchymal stromal/stem cells (MSC) are promising candidates for cellular therapy of different diseases in humans and in animals. Following the guidelines of the International Society for Cell Therapy, human MSC may be identified by expression of a specific panel of cell surface markers (CD105+, CD73+, CD90+, CD34-, CD14-, or CD11b-, CD79- or CD19-, HLA-DR-). In addition, multiple differentiation potential into at least the osteogenic, adipogenic, and chondrogenic lineage is a main criterion for MSC definition. Human MSC and MSC of a variety of mammals isolated from different tissues meet these criteria. In addition to the abovementioned, they express many more cell surface markers. Yet, these are not uniquely expressed by MSC. The gross phenotypic appearance like marker expression and differentiation potential is similar albeit not identical for MSC from different tissues and species. Similarly, MSC may feature different biological characteristics depending on the tissue source and the isolation and culture procedures. Their versatile biological qualities comprising immunomodulatory, anti-inflammatory, and proregenerative capacities rely largely on the migratory and secretory capabilities of MSC. They are attracted to sites of tissue lesion and secrete factors to promote self-repair of the injured tissue. This is a big perspective for clinical MSC applications in both veterinary and human medicine. Phase I/II clinical trials have been initiated to assess safety and feasibility of MSC therapies in acute and chronic disease settings. Yet, since the mode of MSC action in a specific disease environment is still unknown at large, it is mandatory to unravel the response of MSC from a given source onto a specific disease environment in suitable animal models prior to clinical applications. © 2017 International Society for Advancement of Cytometry.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/cyto.a.23239

Mammalian MSC from selected species: Features and applications.

Background Correct development of the placenta is critical to establishing pregnancy and inadequate placentation leads to implantation failure and miscarriage, as well as later gestation pregnancy disorders. Much attention has been focused on the placental trophoblasts and it is clear that the trophoblast lineages arise from the trophectoderm of the blastocyst. In contrast, the cells of the placental mesenchyme are thought to arise from the inner cell mass, but the details of this process are limited. Due to ethical constraints and the inaccessibility of very early implantation tissues, our knowledge of early placentation has been largely based on historical histological sections. More recently, stem cell technologies have begun to shed important new light on the origins of the placental mesenchymal lineages. Objective and rationale This review aims to amalgamate the older and more modern literature regarding the origins of the non-trophoblast lineages of the human placenta. We highlight ways in which rapidly developing stem cell technologies may shed new light on these crucial peri-implantation events. Search methods Relevant articles were identified using the PubMed database and Google Scholar search engines. A pearl growing method was used to expand the scope of papers relevant to the cell differentiation events of non-trophoblast placental lineages. Outcomes At the start of pregnancy, cells of the extraembyronic mesoderm migrate to underlie the primitive trophoblast layers forming the first placental villi. The mesenchymal cells in the villus core most likely originate from the hypoblast of the embryo, but whether cells from the epiblast also contribute is yet to be determined. This is important because, following the formation of the villus core, vasculogenesis and haematopoiesis take place in the nascent placenta before it is connected to the embryonic circulation, making it likely that haematopoietic foci, placental macrophages, endothelial cells and vascular smooth muscle cells all arise in the placenta de novo. Evidence from the stem cell field indicates that these cells could directly differentiate from the extraembryonic mesoderm. However, the lineage hierarchy involved in cell fate decisions has not been well-established. Mesodermal progenitors capable of differentiating into both vascular and haematopoietic lineages can be derived from human embryonic stem cells, but the identification of such stem cells in the placenta is lacking. Future work profiling rare progenitor populations in early placentae will aid our understanding of early placentation. Wider implications Understanding the origins of the cell lineages of the normal placenta will help us understand why so many pregnancies fail and address mechanisms that may salvage some of these losses.

Placental formation in early pregnancy: how is the centre of the placenta made?

Myelomeningocele (MMC)—commonly known as spina bifida—is a congenital birth defect that causes lifelong paralysis, incontinence, musculoskeletal deformities, and severe cognitive disabilities. The recent landmark Management of Myelomeningocele Study (MOMS) demonstrated for the first time in humans that in utero surgical repair of the MMC defect improves lower limb motor function, suggesting a capacity for improved neurologic outcomes in this disorder. However, functional recovery was incomplete, and 58% of the treated children were unable to walk independently at 30 months of age. In the present study, we demonstrate that using early gestation human placenta-derived mesenchymal stromal cells (PMSCs) to augment in utero repair of MMC results in significant and consistent improvement in neurologic function at birth in the rigorous fetal ovine model of MMC. In vitro, human PMSCs express characteristic MSC markers and trilineage differentiation potential. Protein array assays and enzyme-linked immunosorbent assay show that PMSCs secrete a variety of immunomodulatory and angiogenic cytokines. Compared with adult bone marrow MSCs, PMSCs secrete significantly higher levels of brain-derived neurotrophic factor and hepatocyte growth factor, both of which have known neuroprotective capabilities. In vivo, functional and histopathologic analysis demonstrated that human PMSCs mediate a significant, clinically relevant improvement in motor function in MMC lambs and increase the preservation of large neurons within the spinal cord. These preclinical results in the well-established fetal ovine model of MMC provide promising early support for translating in utero stem cell therapy for MMC into clinical application for patients.

https://stemcellsjournals.onlinelibrary.wiley.com/doi/pdf/10.5966/sctm.2014-0296

Placental Mesenchymal Stromal Cells Rescue Ambulation in Ovine Myelomeningocele

Following their discovery over 50 years ago, mesenchymal stromal cells (MSCs) have become one of the most studied cellular therapeutic products by both academia and industry due to their regenerative potential and immunomodulatory properties. The promise of MSCs as a therapeutic modality has been demonstrated by preclinical data yet has not translated to consistent, successful clinical trial results in humans. Despite the disparities across the field, MSC shareholders are unified under one common goal-to use MSCs as a therapeutic modality to improve the quality of life for those suffering from a malady in which the standard of care is suboptimal or no longer effective. Currently, there is no Food and Drug Administration (FDA)-approved MSC therapy on the market in the United States although several MSC products have been granted regulatory approval in other countries. In this review, we intend to identify hurdles that are impeding therapeutic progress and discuss strategies that may aid in accomplishing this universal goal of widespread therapeutic use.

/pdf/therapeutic-use-of-mesenchymal-stromal-cells-the-need-for-3gifvpmknm.pdf

Therapeutic Use of Mesenchymal Stromal Cells: The Need for Inclusive Characterization Guidelines to Accommodate All Tissue Sources and Species

Manufacture and preparation of human placenta-derived mesenchymal stromal cells for local tissue delivery.

Spinal cord injury (SCI) is a devastating disorder that affects humans and dogs. The prognosis of SCI depends on the severity of the injury and can include varying levels of motor and sensory deficits including devastating paraplegia and quadriplegia. Placental mesenchymal stromal cells (PMSCs) have been shown to improve wound healing and possess neuroprotective and immunomodulatory capabilities, but have not yet been clinically tested for the treatment of SCI. This study established a protocol to isolate fetal PMSCs from canine placentas and characterized their paracrine secretion profile and ability to stimulate neurons in vitro to assess their potential as a treatment option for neurological disorders in dogs. Canine PMSCs (cPMSCs) were plastic adherent and capable of trilineage differentiation. cPMSCs expressed typical MSC markers and did not express hematopoietic or endothelial cell markers. Genotyping of cPMSCs revealed fetal rather than maternal origin of the cells. cPMSCs were viable and mitotically expansive in a collagen hydrogel delivery vehicle, and they secreted the immunomodulatory and neurotrophic paracrine factors interleukin (IL)-6, IL-8, monocyte chemoattractant protein 1 (MCP-1), and vascular endothelial growth factor (VEGF). cPMSCs also stimulated the growth of complex neural networks when co-cultured with SH-SY5Y cells, a neuroblastoma cell line used to model neuron growth in vitro. cPMSCs are analogous to human PMSCs. They meet the criteria to be defined as MSCs and represent a potential regenerative therapy option for neurological disorders in dogs with their robust growth in collagen hydrogel, stimulation of neural network formation, and secretion of potent paracrine factors. © 2017 International Society for Advancement of Cytometry.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/cyto.a.23171

Isolation and characterization of canine placenta-derived mesenchymal stromal cells for the treatment of neurological disorders in dogs.

Stem cell-based in utero therapies for spina bifida: implications for neural regeneration.

Q fever is a worldwide zoonosis caused by Coxiella burnetii that can lead to abortion, endocarditis, and death in humans. Researchers utilizing parturient domestic ruminants, including sheep, have ...

Minimizing the risk of occupational Q fever exposure: A protocol for ensuring Coxiella burnetii–negative pregnant ewes are used for medical research:

Women have made serious advances in the fields of medicine and surgery in the recent past, but 160 years after Elizabeth Blackwell’s graduation from medical school, society is still far from gender parity. Although women now constitute roughly 50 % of American medical students and enter academic medicine as faculty in numbers equal to their male colleagues, women are grossly underrepresented in positions of power and leadership, especially in surgery. In this chapter, the authors provide the data regarding leadership by women in surgery, discuss gender roles, sexism, and mentorship and how they impact the ability of women to lead, and provide their own personal leadership journeys.

Women as Leaders in Surgery

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