• adult stem cells
• cell signalling

• P01 HL147841 NHLBI NIH HHS
• R01 HL091983 NHLBI NIH HHS
• R01 HL143892 NHLBI NIH HHS
• P01 HL134608 NHLBI NIH HHS
• U.S. Department of Health & Human Services | National Institutes of Health (NIH)

• Heterogeneity
• MSCs
• Mesenchymal stem/stromal cells
• Potency
• Sex

• Humans
• Mesenchymal Stem Cells/cytology
• Mesenchymal Stem Cells/metabolism
• Mesenchymal Stem Cell Transplantation/methods
• Female
• Tissue Donors
• Cell Differentiation
• Male
• Sex Factors

• R01 DK120394 NIDDK NIH HHS
• R01 DK105183 NIDDK NIH HHS
• 1R01DK105183, DK120394, DK118529 NIDDK NIH HHS
• R01 DK118529 NIDDK NIH HHS
• I01 BX004536 BLRD VA
• I01 CX002516 CSRD VA
• R01 DK126454 NIDDK NIH HHS
• National Institute of Diabetes and Digestive and Kidney Diseases
• U.S. Department of Veterans Affairs

• adipose derived stem cells
• bone marrow mesenchymal stromal cells
• estrogen
• musculoskeletal stem cells
• sexual dimorphism

• Adult
• Bone and Bones
• Cell Differentiation
• Estrogens
• Female
• Humans
• Male
• Sex Characteristics
• Stem Cells
• Tissue Engineering

• P20 GM103638 NIGMS NIH HHS
• R35 GM143081 NIGMS NIH HHS
• UL1 TR002366 NCATS NIH HHS

Mesenchymal stromal/stem cells (MSCs) are currently being used in clinical trials as proposed treatments for a large range of genetic, immunological, orthopaedic, cardiovascular, endocrine and neurological disorders. MSCs are potent anti-inflammatory mediators which are considered immune evasive and employ a large range of secreted vesicles to communicate and repair damaged tissue. Despite their prolific use in therapy, sex specific mechanism of action is rarely considered as a potential confounding factor for use. The purpose of this study was to examine the potency and functionality of both female and male adipose derived MSCs in order to gain further insights into donor selection. Methods MSC were expanded to passage 4, secretome was harvested and stored at − 80c. To assess potency MSC were also primed and assessed via functional immune assays, ELISA, multiplex and immunophenotyping. Results Female MSCs (fMSC), consistently suppressed Peripheral blood mononuclear cell (PBMC) proliferation significantly (p < 0.0001) more than male MSC (mMSC). In co-culture mPBMCs, showed 60.7 ± 15.6% suppression with fMSCs compared with 22.5 ± 13.6% suppression with mMSCs. Similarly, fPBMCs were suppressed by 67.9 ± 10.4% with fMSCs compared to 29.4 ± 9.3% with mMSCs. The enhanced immunosuppression of fMSCs was attributed to the production of higher concentrations of the anti-inflammatory mediators such as IDO1 (3301 pg/mL vs 1699 pg/mL) and perhaps others including IL-1RA (1025 pg/mL vs 701 pg/mL), PGE-2 (6142 pg/mL vs 2448 pg/mL) and prolonged expression of VCAM-1 post activation relative to mMSCs. In contrast, mMSCs produces more inflammatory G-CSF than fMSCs (806 pg/mL vs 503 pg/mL). Moreover, IDO1 expression was correlated to immune suppression and fMSCs, but not mMSCs induced downregulation of the IL-2 receptor and sustained expression of the early T cell activation marker, CD69 in PBMCs further highlighting the differences in immunomodulation potentials between the sexes. Conclusion In conclusion, our data shows that female MSC are more potent in vitro than their male counterparts. The inability of male MSC to match female MSC driven immunomodulation and to use the inflammatory microenvironment to their advantage is evident and is likely a red flag when using allogeneic male MSC as a therapeutic for disease states.

• PLacental eXpanded
• coronavirus-induced disease 2019
• mesenchymal stromal cells
• perinatal
• severe acute respiratory distress syndrome coronavirus-2

Despite recent advances in neonatal care, sepsis remains a leading cause of mortality in neonates. Mesenchymal stem cells derived from various tissues, such as bone marrow, umbilical cord, and adipose tissue, have beneficial effects on adult sepsis. Although human amniotic fluid stem cells (hAFSCs) have mesenchymal stem cell properties, the efficacy of hAFSCs on neonatal sepsis is yet to be elucidated. This study aimed to investigate the therapeutic potential of hAFSCs on neonatal sepsis using a rat model of lipopolysaccharide (LPS)-induced sepsis.

hAFSCs were isolated as CD117-positive cells from human amniotic fluid. Three-day-old rat pups were intraperitoneally treated with LPS to mimic neonatal sepsis. hAFSCs were administered either 3 h before or at 0, 3, or 24 h after LPS exposure. Serum inflammatory cytokine levels, gene expression profiles from spleens, and multiple organ damage were analyzed. hAFSC localization was determined in vivo. In vitro LPS stimulation tests were performed using neonatal rat peritoneal macrophages co-cultured with hAFSCs in a cell-cell contact-dependent/independent manner. Immunoregulation in the spleen was determined using a DNA microarray analysis.

Prophylactic therapy with hAFSCs improved survival in the LPS-treated rats while the hAFSCs transplantation after LPS exposure did not elicit a therapeutic response. Therefore, hAFSC pretreatment was used for all subsequent studies. Inflammatory cytokine levels were elevated after LPS injection, which was attenuated by hAFSC pretreatment. Subsequently, inflammation-induced damages in the brain, lungs, and liver were ameliorated. hAFSCs aggregated with peritoneal macrophages and/or transiently accumulated in the liver, mesentery, and peritoneum. Paracrine factors released by hAFSCs induced M1-M2 macrophage polarization in a cell-cell contact-independent manner. Direct contact between hAFSCs and peritoneal macrophages further enhanced the polarization. Microarray analysis of the spleen showed that hAFSC pretreatment reduced the expression of genes involved in apoptosis and inflammation and subsequently suppressed toll-like receptor 4 signaling pathways.

Prophylactic therapy with hAFSCs improved survival in a rat model of LPS-induced neonatal sepsis. These effects might be mediated by a phenotypic switch from M1 to M2 in peritoneal macrophages, triggered by hAFSCs in a cell-cell contact-dependent/independent manner and the subsequent immunomodulation of the spleen.

• Human amniotic fluid stem cells
• Immunomodulation
• Inflammatory cytokines
• Macrophage polarization
• Mesenchymal stem cells
• Neonatal sepsis

• Wharton’s jelly-derived mesenchymal stem cells
• autonomic dysfunction
• cholinergic anti-inflammatory pathway
• heart rate variability
• sepsis-induced organ injury
• α7-nicotinic acetylcholine receptor

• Exosomes
• Extracellular vesicles
• Mesenchymal stromal (stem) cells
• Mesenchymal stromal cell-derived extracellular vesicles
• Sepsis

Sex differences are important epidemiological factors that impact in the frequency and severity of infectious diseases. A clear sexual dimorphism in bacterial infections has been reported in both humans and animal models. Nevertheless, the molecular mechanisms involved in this gender bias are just starting to be elucidated. In the present article, we aim to review the available data in the literature that report bacterial infections presenting a clear sexual dimorphism, without considering behavioral and social factors.

The sexual dimorphism in bacterial infections has been mainly attributed to the differential levels of sex hormones between males and females, as well as to genetic factors. In general, males are more susceptible to gastrointestinal and respiratory bacterial diseases and sepsis, while females are more susceptible to genitourinary tract bacterial infections. However, these incidences depend on the population evaluated, animal model and the bacterial species. Female protection against bacterial infections and the associated complications is assumed to be due to the pro-inflammatory effect of estradiol, while male susceptibility to those infections is associated with the testosterone-mediated immune suppression, probably via their specific receptors. Recent studies indicate that the protective effect of estradiol depends on the estrogen receptor subtype and the specific tissue compartment involved in the bacterial insult, suggesting that tissue-specific expression of particular sex steroid receptors contributes to the susceptibility to bacterial infections. Furthermore, this gender bias also depends on the effects of sex hormones on specific bacterial species. Finally, since a large number of genes related to immune functions are located on the X chromosome, X-linked mosaicism confers a highly polymorphic gene expression program that allows women to respond with a more expanded immune repertoire as compared with men.

Notwithstanding there is increasing evidence that confirms the sexual dimorphism in certain bacterial infections and the molecular mechanisms associated, further studies are required to clarify conflicting data and to determine the role of specific hormone receptors involved in the gender bias of bacterial infections, as well as their potential as therapeutic targets.

• Bacterial infection
• Estradiol
• Progesterone
• Sex steroid hormones
• Sexual dimorphism
• Testosterone

• Animals
• Cell Lineage
• Diabetes Mellitus, Type 2/complications
• Diabetes Mellitus, Type 2/physiopathology
• Diabetes Mellitus, Type 2/therapy
• Diabetic Angiopathies/etiology
• Diabetic Cardiomyopathies/physiopathology
• Diabetic Cardiomyopathies/therapy
• Diabetic Retinopathy/physiopathology
• Diabetic Retinopathy/therapy
• Humans
• Hyperglycemia/complications
• Insulin/metabolism
• Insulin Resistance
• Mice
• Microcirculation
• Nitrosative Stress
• Oxidative Stress
• Signal Transduction
• Stem Cell Transplantation
• Stem Cells/cytology
• Wound Healing

Sepsis, newly defined as a life-threatening organ dysfunction caused by a dysregulated host response to infection, is the most common cause of death in ICUs and one of the principal causes of death worldwide. Although substantial progress has been made in the understanding of fundamental mechanisms of sepsis, translation of these advances into clinically effective therapies has been disappointing. Given the extreme complexity of sepsis pathogenesis, the paradigm “one disease, one drug” is obviously flawed and combinations of multiple targets that involve early immunomodulation and cellular protection are needed. In this context, the immune-reprogramming properties of cell-based therapy using mesenchymal stem cells (MSC) represent an emerging therapeutic strategy in sepsis and associated organ dysfunction. This article provides an update of the current knowledge regarding MSC in preclinical models of sepsis and sepsis-induced acute kidney injury. Recommendations for further translational research in this field are discussed.

• Mesenchymal stem cells
• Mitochondria
• Mitochondrial DNA
• Muscle stem cells
• Sepsis

Mesenchymal stem cells (MSC) improve alveolar and vascular structures in experimental models of bronchopulmonary dysplasia (BPD). Female MSC secrete more anti-inflammatory and pro-angiogenic factors as compared to male MSC. Whether the therapeutic efficacy of MSC in attenuating lung injury in an experimental model of BPD is influenced by the sex of the donor MSC or recipient is unknown. Here we tested the hypothesis that female MSC would have greater lung regenerative properties than male MSC in experimental BPD and this benefit would be more evident in males.

To determine whether intra-tracheal (IT) administration of female MSC to neonatal rats with experimental BPD has more beneficial reparative effects as compared to IT male MSC.

Newborn Sprague-Dawley rats exposed to normoxia (RA) or hyperoxia (85% O2) from postnatal day (P) 2- P21 were randomly assigned to receive male or female IT bone marrow (BM)-derived green fluorescent protein (GFP⁺) MSC (1 x 10⁶ cells/50 μl), or Placebo on P7. Pulmonary hypertension (PH), vascular remodeling, alveolarization, and angiogenesis were assessed at P21. PH was determined by measuring right ventricular systolic pressure (RVSP) and pulmonary vascular remodeling was evaluated by quantifying the percentage of muscularized peripheral pulmonary vessels. Alveolarization was evaluated by measuring mean linear intercept (MLI) and radial alveolar count (RAC). Angiogenesis was determined by measuring vascular density. Data are expressed as mean ± SD, and analyzed by ANOVA.

There were no significant differences in the RA groups. Exposure to hyperoxia resulted in a decrease in vascular density and RAC, with a significant increase in MLI, RVSP, and the percentage of partially and fully muscularized pulmonary arterioles. Administration of both male and female MSC significantly improved vascular density, alveolarization, RVSP, percent of muscularized vessels and alveolarization. Interestingly, the improvement in PH and vascular remodeling was more robust in the hyperoxic rodents who received MSC from female donors. In keeping with our hypothesis, male animals receiving female MSC, had a greater improvement in vascular remodeling. This was accompanied by a more significant decrease in lung pro-inflammatory markers and a larger increase in anti-inflammatory and pro-angiogenic markers in male rodents that received female MSC. There were no significant differences in MSC engraftment among groups.

Female BM-derived MSC have greater therapeutic efficacy than male MSC in reducing neonatal hyperoxia-induced lung inflammation and vascular remodeling. Furthermore, the beneficial effects of female MSC were more pronounced in male animals. Together, these findings suggest that female MSC maybe the most potent BM-derived MSC population for lung repair in severe BPD complicated by PH.

• Animals
• Animals, Newborn
• Blood Pressure
• Bone Marrow Cells/cytology
• Bronchopulmonary Dysplasia/etiology
• Bronchopulmonary Dysplasia/therapy
• Cells, Cultured
• Disease Models, Animal
• Female
• Hyperoxia
• Hypertension, Pulmonary/complications
• Interleukin-10/metabolism
• Lung/pathology
• Male
• Mesenchymal Stem Cell Transplantation
• Mesenchymal Stem Cells/cytology
• Mesenchymal Stem Cells/metabolism
• Neovascularization, Physiologic
• Pulmonary Alveoli/physiology
• Rats
• Rats, Sprague-Dawley
• Vascular Endothelial Growth Factor A/metabolism
• Vascular Remodeling

• Batchelor Research Foundation
• Project Newborn-UM/JMH

• Multiple organ dysfunction
• Pathophysiology
• Pluripotency
• Sepsis
• Stem cells
• Therapeutic intervention

Sepsis is a clinical syndrome caused by a deregulated host response to an infection. Sepsis is the most frequent cause of death in hospitalized patients. Although knowledge of the pathogenesis of sepsis has increased substantially during the last decades, attempts to design effective and specific therapies targeting components of the derailed host response have failed. Therefore, there is a dramatic need for new and mechanistically alternative therapies to treat this syndrome. Based on their immunomodulatory properties, adult mesenchymal stem or stromal cells (MSCs) can be a novel therapeutic tool to treat sepsis. Indeed, MSCs reduce mortality in experimental models of sepsis by modulating the deregulated inflammatory response against bacteria through the regulation of multiple inflammatory networks, the reprogramming of macrophages and neutrophils towards a more anti-inflammatory phenotype and the release of anti-microbial peptides. This report will review the current knowledge on the effects of MSC treatment in preclinical experimental small animal models of sepsis.

• Adult mesenchymal stem cells
• Therapy
• Sepsis