Quantitative Metabolomics and Lipoprotein Analysis of PDAC Patients Suggests Serum Marker Categories for Pancreatic Function, Pancreatectomy, Cancer Metabolism, and Systemic Disturbances.

Pancreatic ductal adenocarcinoma (PDAC) is difficult to diagnose in the early stages and lacks reliable biomarkers. The scope of this project was to establish quantitative nuclear magnetic resonance (NMR) spectroscopy to comprehensively study blood serum alterations in PDAC patients. Serum samples from 34 PDAC patients obtained before and after pancreatectomy as well as 83 age- and sex-matched control samples from healthy donors were analyzed with in vitro diagnostics research (IVDr) proton NMR spectroscopy at 600 MHz. Uni- and multivariate statistics were applied to identify significant biofluid alterations. We identified 29 significantly changed metabolites and 98 lipoproteins when comparing serum from healthy controls with those of PDAC patients. The most prominent features were assigned to (i) markers of pancreatic function (e.g., glucose and blood triglycerides), (ii) markers related to surgery (e.g., ketone bodies and blood cholesterols), (iii) PDAC-associated markers (e.g., amino acids and creatine), and (iv) markers for systemic disturbances in PDAC (e.g., gut metabolites DMG, TMAO, DMSO2, and liver lipoproteins). Quantitative serum NMR spectroscopy is suited as a diagnostic tool to investigate PDAC. Remarkably, 2-hydroxybutyrate (2-HB) as a previously suggested marker for insulin resistance was found in extraordinarily high levels only after pancreatectomy, suggesting this metabolite is the strongest marker for pancreatic loss of function.

Late Local Recurrence after Neoadjuvant Therapy and Radical Resection for Locally Advanced Rectal Cancer.

Neoadjuvant radiochemotherapy (RCT) and lately total neoadjuvant therapy (TNT) improved local recurrence rates of rectal cancer significantly compared to total mesorectal excision (TME) alone. Yet the occurrence and impact of late local recurrences after many years appears to be a distinct biological problem. We included n = 188 patients with rectal cancer after RCT and radical resection in this study; n = 38 of which had recurrent disease (sites: local (8.0%), liver (6.4%), lung (3.7%)). We found that 68% of all recurrences developed within the first two years. Four patients, however, experience recurrence >8 years after surgery. Here, we report and characterize four cases of late local recurrence (10% of patients with recurrent disease), suggesting that neoadjuvant therapy in principle delays local recurrence.

Mesenchymal Stromal Cell-Based Therapy.

The use of mesenchymal stromal cells (MSCs) for clinical application is intensively investigated for a variety of areas, such as bone repair, haematological and autoimmune diseases, and solid organ transplantation [...].

Establishing a New Platform to Investigate the Efficacy of Oncolytic Virotherapy in a Human Ex Vivo Peritoneal Carcinomatosis Model.

Oncolytic virotherapy constitutes a promising treatment option for many solid cancers, including peritoneal carcinomatosis (PC), which still represents a terminal stage of many types of tumors. To date, the in vitro efficacy of oncolytic viruses is mostly tested in 2D-cultured tumor cell lines due to the lack of realistic 3D in vitro tumor models. We have investigated the feasibility of virotherapy as a treatment option for PC in a human ex vivo peritoneum co-culture model. Human HT-29 cancer cells stably expressing marker genes GFP and firefly luciferase (GFP/luc) were cultured on human peritoneum and infected with two prototypic oncolytic viruses (GLV-0b347 and MeV-DsRed). Both viral constructs were able to infect HT-29 cells in patient-derived peritoneum with high tumor specificity. Over time, both GFP signal and luciferase activity decreased substantially, thereby indicating successful virus-induced oncolysis. Furthermore, immunohistochemistry stainings showed specific virotherapeutic infections of HT-29 cells and effective tumor cell lysis in infected co-cultures. Thus, the PC model established here provides a clinically relevant screening platform to evaluate the therapeutic efficacy of virotherapeutic compounds and also to investigate, in an autologous setting, the immunostimulatory potential of oncolytic viruses for PC in a unique human model system superior to standard 2D in vitro models.

Pharmacologic Targeting of MMP2/9 Decreases Peritoneal Metastasis Formation of Colorectal Cancer in a Human Ex Vivo Peritoneum Culture Model.

BACKGROUND: Matrix metalloproteinases (MMPs) play a crucial role in tumour initiation, progression, and metastasis, including peritoneal carcinosis (PC) formation. MMPs serve as biomarkers for tumour progression in colorectal cancer (CRC), and MMP overexpression is associated with advanced-stage metastasis and poor survival. However, the molecular mechanisms of PC from CRC remain largely unclear. METHODS: We investigated the role of MMPs during peritoneal colonisation by CRC cell lines in a human ex vivo peritoneum model and in patient-derived CRC and corresponding PC samples. MMP2 and MMP9 were inhibited using the small-molecule inhibitors batimastat and the specific MMP2/9 inhibitor III. RESULTS: MMP2 and MMP9 were strongly upregulated in patient-derived samples and following peritoneal colonisation by CRC cells in the ex vivo model. MMP inhibition with batimastat reduced colonisation of HT29 and Colo205 cells by 36% and 68%, respectively (p = 0.0073 and p = 0.0002), while MMP2/9 inhibitor III reduced colonisation by 50% and 41%, respectively (p = 0.0003 and p = 0.0051). Fibronectin cleavage was enhanced in patient-derived samples of PC and during peritoneal colonisation in the ex vivo model, and this was inhibited by MMP2/9 inhibition. CONCLUSION: MMPs were upregulated in patient-derived samples and during peritoneal attachment of CRC cell lines in our ex vivo model. MMP2/9 inhibition prevented fibronectin cleavage and peritoneal colonisation by CRC cells. MMP inhibitors might thus offer a potential treatment strategy for patients with PC.

How to Make Sense out of 75,000 Mesenchymal Stromal Cell Publications?

Mesenchymal stromal cells have been the subject of an expanding number of studies over the past decades. Today, over 75,000 publications are available that shine light on the biological properties and therapeutic effects of these versatile cells in numerous pre-clinical models and early-phase clinical trials. The massive number of papers makes it hard for researchers to comprehend the whole field, and furthermore, they give the impression that mesenchymal stromal cells are wonder cells that are curative for any condition. It is becoming increasingly difficult to dissect how and for what conditions mesenchymal stromal cells exhibit true and reproducible therapeutic effects. This article tries to address the question how to make sense of 75,000, and still counting, publications on mesenchymal stromal cells.

Triple Targeting of HER Receptors Overcomes Heregulin-mediated Resistance to EGFR Blockade in Colorectal Cancer.

Current treatment options for patients with advanced colorectal cancers include anti-EGFR/HER1 therapy with the blocking antibody cetuximab. Although a subset of patients with KRAS WT disease initially respond to the treatment, resistance develops in almost all cases. Relapse has been associated with the production of the ligand heregulin (HRG) and/or compensatory signaling involving the receptor tyrosine kinases HER2 and HER3. Here, we provide evidence that triple-HER receptor blockade based on a newly developed bispecific EGFR×HER3-targeting antibody (scDb-Fc) together with the HER2-blocking antibody trastuzumab effectively inhibited HRG-induced HER receptor phosphorylation, downstream signaling, proliferation, and stem cell expansion of DiFi and LIM1215 colorectal cancer cells. Comparative analyses revealed that the biological activity of scDb-Fc plus trastuzumab was sometimes even superior to that of the combination of the parental antibodies, with PI3K/Akt pathway inhibition correlating with improved therapeutic response and apoptosis induction as seen by single-cell analysis. Importantly, growth suppression by triple-HER targeting was recapitulated in primary KRAS WT patient-derived organoid cultures exposed to HRG. Collectively, our results provide strong support for a pan-HER receptor blocking approach to combat anti-EGFR therapy resistance of KRAS WT colorectal cancer tumors mediated by the upregulation of HRG and/or HER2/HER3 signaling.

A human ex vivo coculture model to investigate peritoneal metastasis and innovative treatment options.

OBJECTIVES: Peritoneal metastasis (PM) is commonly observed in patients with colorectal cancer (CRC). The outcome of these patients is poor, with an average survival of only six months without therapy, which requires a better understanding of PM biology and new treatment strategies. METHODS: We established and characterized a human ex vivo peritoneal model to investigate the mechanisms of peritoneal seeding and possible treatment options. For this, CRC cell lines and patient-derived tumor organoids were cultured together with human peritoneum to investigate the invasion of malignant cells and the effects of local chemotherapy. RESULTS: Fresh human peritoneum was cultured for up to three weeks in a stainless steel ring system, allowing for survival of all peritoneal structures. Peritoneal cell survival was documented by light microscopy and immunohistochemical staining. Further, immunohistological characterization of the tissue revealed CD3-positive T-lymphocytes and vimentin-positive fibroblasts within the peritoneum. In addition, extracellular matrix components (collagens, matrix metalloproteinases) were localized within the tissue. Coculture with CRC cell lines and patient-derived CRC organoids revealed that cancer cells grew on the peritoneum and migrated into the tissue. Coculture with CRC cells confirmed that hyperthermal treatment at 41 °C for 90 min significantly enhanced the intracellular entry of doxorubicin. Moreover, treatment with mitomycin C under hyperthermic conditions significantly reduced the amount of cancer cells within the peritoneum. CONCLUSIONS: This human ex vivo peritoneal model provides a stringent and clinically relevant platform for the investigation of PM and for further elucidation of possible treatment options.

Three dimensional cultivation increases chemo- and radioresistance of colorectal cancer cell lines.

Although 2D cell cultures are commonly used to predict therapy response, it has become clear that 3D cultures may better mimic the in vivo situation and offer the possibility of tailoring translational clinical approaches. Here, we compared the response of 2D and 3D colorectal cancer (CRC) cell lines to irradiation and chemotherapy. Classic 2D cultures and 3D spheroids of CRC cell lines (CaCo2, Colo205, HCT116, SW480) were thoroughly established, then irradiated with doses of 1, 4, or 10 Gy, using a clinical-grade linear accelerator. The response was assessed by immunohistochemistry, flow cytometry, and TUNEL assays. Upon irradiation, CRC 3D spheroids were morphologically altered. After irradiation with 10 Gy, annexin V/PI staining revealed a 1.8- to 4-fold increase in the apoptosis rate in the 2D cell cultures (95% CI 3.24±0.96), and a 1.5- to 2.4-fold increase in the 3D spheroids (95% CI 1.56±0.41). Irradiation with 1 Gy caused 3- and 4-fold increases in TUNEL positive cells in the CaCo2 and HCT116 (p = 0.01) 2D cultures, respectively, compared with a 2-fold increase in the 3D spheroids. Furthermore, the 2D and 3D cultures responded differently to chemotherapy; the 3D cultures were more resistant to 5-FU and cisplatin, but not to doxorubicin and mitomycin C, than the 2D cultures. Taken together, CRC cells cultured as 3D spheroids displayed markedly higher resistance to irradiation therapy and selected chemotherapeutic drugs than 2D cultures. This in vitro difference must be considered in future approaches for determining the ideal in vitro systems that mimic human disease.

Surgical Site Infections and their economic significance in hepatopancreatobiliary surgery: A retrospective incidence, cost, and reimbursement analysis in a German centre of the highest level of care.

Surgical site infections (SSI) in open Hepatopancreatobiliary (HPB) surgery are common complications. They worsen patients' outcomes and prolong hospital stays. Their economic significance in the German diagnosis related groups (DRG) system is mostly unknown. To investigate their economic importance, we evaluated all cases for SSIs as well as clinical and financial parameters undergoing surgery in our centre from 2015 and 2016. Subsequently, we carried out a cost-revenue calculation by assessing our billing data and the cost matrix of the InEK (German Institute for the Payment System in Hospitals). A total of 13.5% of the patients developed a superficial, 9% a deep incisional, and 2.4% of the patients an organ space SSI. Compared with Patients without SSI, Patients with SSI had more comorbidities, were older, and their average length of stay was extended by 19 days (P < .001). The financial loss per SSI-case was €-7035.65 despite increased reimbursement, which resulted in a calculated total loss for the hospital of €-802 064.62 in 2015 and 2016. Surgical site infections are common complications of open HPB surgery, which lead to a significant increase in the cost per case. Further prevention strategies need to be developed. Besides, an adjustment of revenues must be demanded.

Metabolic Drug Response Phenotyping in Colorectal Cancer Organoids by LC-QTOF-MS.

As metabolic rewiring is crucial for cancer cell proliferation, metabolic phenotyping of patient-derived organoids is desirable to identify drug-induced changes and trace metabolic vulnerabilities of tumor subtypes. We established a novel protocol for metabolomic and lipidomic profiling of colorectal cancer organoids by liquid chromatography quadrupole time-of-flight mass spectrometry (LC-QTOF-MS) facing the challenge of capturing metabolic information from a minimal sample amount (<500 cells/injection) in the presence of an extracellular matrix (ECM). The best procedure of the tested protocols included ultrasonic metabolite extraction with acetonitrile/methanol/water (2:2:1, v/v/v) without ECM removal. To eliminate ECM-derived background signals, we implemented a data filtering procedure based on the p-value and fold change cut-offs, which retained features with signal intensities >120% compared to matrix-derived signals present in blank samples. As a proof-of-concept, the method was applied to examine the early metabolic response of colorectal cancer organoids to 5-fluorouracil treatment. Statistical analysis revealed dose-dependent changes in the metabolic profiles of treated organoids including elevated levels of 2'-deoxyuridine, 2'-O-methylcytidine, inosine and 1-methyladenosine and depletion of 2'-deoxyadenosine and specific phospholipids. In accordance with the mechanism of action of 5-fluorouracil, changed metabolites are mainly involved in purine and pyrimidine metabolism. The novel protocol provides a first basis for the assessment of metabolic drug response phenotypes in 3D organoid models.

The emergence of regenerative medicine in organ transplantation: 1st European Cell Therapy and Organ Regeneration Section meeting.

Regenerative medicine is emerging as a novel field in organ transplantation. In September 2019, the European Cell Therapy and Organ Regeneration Section (ECTORS) of the European Society for Organ Transplantation (ESOT) held its first meeting to discuss the state-of-the-art of regenerative medicine in organ transplantation. The present article highlights the key areas of interest and major advances in this multidisciplinary field in organ regeneration and discusses its implications for the future of organ transplantation.

Differential effects of heat-inactivated, secretome-deficient MSC and metabolically active MSC in sepsis and allogenic heart transplantation.

Mesenchymal stem cells (MSCs) are used in various clinical and preclinical models for immunomodulation. However, it remains unclear how the immunomodulatory effect of MSC is communicated. MSC-induced immunomodulation is known to be mediated through both MSC-secreted cytokines and direct cell-cell interactions. Recently, it has been demonstrated that metabolically inactive, heat-inactivated MSCs (HI-MSCs) have similar anti-inflammatory capacities in LPS-induced sepsis compared with viable MSC. To further investigate the immunomodulatory effects of MSC, we introduced MSC and HI-MSC in two animal models with different immunological causes. In the first model, allogeneic hearts were transplanted from C57BL/6 mice to BALB/c recipients. MSC in combination with mycophenolate mofetil (MMF) significantly improved graft survival compared with MMF alone, whereas the application of HI-MSC had no effect on graft survival. We revealed that control MSC dose-dependently inhibited CD3+ and CD8+ T-cell proliferation in vitro, whereas HI-MSC had no effect. In the second model, sepsis was induced in mice via cecal ligation and puncture. HI-MSC treatment significantly improved the overall survival, whereas control MSCs had no effect. in vitro studies demonstrated that HI-MSCs are more effectively phagocytosed by monocytes than control MSCs and induced cell death in particular of activated CD16+ monocytes, which may explain the immune protective effect of HI-MSC in the sepsis model. The results of our study demonstrate that MSC-mediated immunomodulation in sepsis is dependent on a passive recognition of MSC by monocytes, whereas fully functional MSCs are required for inhibition of T-cell-mediated allograft rejection.

Immunomodulation by Mesenchymal Stem Cells (MSCs): Mechanisms of Action of Living, Apoptotic, and Dead MSCs.

Expectations on mesenchymal stem cell (MSC) treatment are high, especially in the fields of sepsis, transplant medicine, and autoimmune diseases. Various pre-clinical studies have been conducted with encouraging results, although the mechanisms of action behind the observed immunomodulatory capacity of mesenchymal stem cells have not been fully understood. Previous studies have demonstrated that the immunomodulatory effect of MSCs is communicated via MSC-secreted cytokines and has been proven to rely on the local microenvironment as some of the observed effects depend on a pre-treatment of MSCs with inflammatory cytokines. Nonetheless, recent findings indicate that the cytokine-mediated effects are only one part of the equation as apoptotic, metabolically inactivated, or even fragmented MSCs have been shown to possess an immunomodulatory potential as well. Both cytokine-dependent and cytokine-independent mechanisms suggest a key role for regulatory T cells and monocytes in the overall pattern, but the principle as to why viable and non-viable MSCs have similar immunomodulatory capacities remains elusive. Here we review the current knowledge on cellular and molecular mechanisms involved in MSC-mediated immunomodulation and focus on the viability of MSCs, as there is still uncertainty concerning the tumorigenic potential of living MSCs.

DWI - histology: a possible means of determining degree of liver fibrosis?

OBJECTIVES: The aim of this study was to determine the diagnostic value of diffusion-weighted MRI of the liver at 3T to classify liver fibrosis/cirrhosis. METHODS: 62 patients who underwent both histopathological examination and diffusion-weighted imaging of the liver via 3T MRI within a period of 3 months were included in the study. The Ishak score (1-6) was used to determine the degree of fibrosis: No liver fibrosis (NLF; Ishak 0, n = 16), mild liver fibrosis (MLF; Ishak 1-2, n = 23), advanced liver fibrosis (ALF; Ishak 3-5, n = 12), and liver cirrhosis (LC; Ishak 6, n = 11). RESULTS: The corresponding ADC values for the individual patient groups were as follows: NLF: 1123 (SD 95.8); MLF: 1032 (SD 77.6); ALF: 962 (SD 68.8); LC: 1015 (SD 60.2) mm2/s. There is a significant difference between NLF and MLF (p = 0.004) and between MLF and ALF (p = 0.022). A significant difference between patients with ALF and LC (p = 0.117) could not be found. CONCLUSION: Liver fibrosis/cirrhosis lowers the ADC values of the liver parenchyma in 3T MRI. However, the degree of fibrosis can only be conditionally determined on the basis of ADC values.

Detecting liver fibrosis with Gd-EOB-DTPA-enhanced MRI: A confirmatory study.

Strong correlations between the grade of fibrosis and cirrhosis, classified using the Ishak scoring system, and the uptake characteristics of Gd-EOB-DTPA with the relative enhancement (RE) of the liver parenchyma have been reported. To confirm the results of a retrospective analysis, patients undergoing liver surgery were prospectively examined with Gd-EOB-DTPA-enhanced liver 3 Tesla MRI to determine the degree of liver fibrosis. Correlations between the grade of fibrosis and cirrhosis, classified using the Ishak scoring system, and RE were investigated and compared with those derived from an initial retrospective study. After validating the cut-off values in the retrospective study (Ishak ≥ 1, RE-cut-off 0.90; Ishak ≥ 2, RE-cut-off 0.79; Ishak ≥ 4, RE-cut-off 0.60; and Ishak = 6, RE-cut-off 0.47), we showed that Gd-EOB-DTPA has a high sensitivity (≥86%) and a high positive predictive value (≥86%). These results support the use of Gd-EOB-DTPA-enhanced liver MRI as a non-invasive method for determining the degree of liver fibrosis and cirrhosis.

Gd-EOB-DTPA-enhanced T1 relaxometry for assessment of liver function determined by real-time 13C-methacetin breath test.

OBJECTIVES: To determine whether liver function as determined by intravenous administration of 13C-methacetin and continuous real-time breath analysis can be estimated quantitatively from gadoxetic acid (Gd-EOB-DTPA)-enhanced magnetic resonance (MR) relaxometry. METHODS: Sixty-six patients underwent a 13C-methacetin breath test (13C-MBT) for evaluation of liver function and Gd-EOB-DTPA-enhanced T1-relaxometry at 3 T. A transverse 3D VIBE sequence with an inline T1 calculation based on variable flip angles was acquired prior to (T1 pre) and 20 min post-Gd-EOB-DTPA (T1 post) administration. The reduction rate of T1 relaxation time (rrT1) and T1 relaxation velocity index (∆R1) between pre- and post-contrast images was evaluated. 13C-MBT values were correlated with T1post, ∆R1 and rrT1, providing an MRI-based estimated 13C-MBT value. The interobserver reliability was assessed by determining the intraclass correlation coefficient (ICC). RESULTS: Stratified by three different categories of 13C-MBT readouts, there was a constant increase of T1 post with increasing progression of diminished liver function (p ≤ 0.030) and a constant significant decrease of ∆R1 (p ≤ 0.025) and rrT1 (p < 0.018) with progression of liver damage as assessed by 13C-methacetin breath analysis. ICC for all T1 relaxation values and indices was excellent (> 0.88). A simple regression model showed a log-linear correlation of 13C-MBT values with T1post (r = 0.57; p < 0.001), ∆R1 (r = 0.59; p < 0.001) and rrT1 (r = 0.70; p < 0.001). CONCLUSION: Liver function as determined using real-time 13C-methacetin breath analysis can be estimated quantitatively from Gd-EOB-DTPA-enhanced MR relaxometry. KEY POINTS: • Gd-EOB-DTPA-enhanced T1 relaxometry quantifies liver function • Gd-EOB-DTPA-enhanced MR relaxometry may provide parameters for assessing liver function before surgery • Gd-EOB-DTPA-enhanced MR relaxometry may be useful for monitoring liver disease progression • Gd-EOB-DTPA-enhanced MR relaxometry has the potential to become a novel liver function index.

Safety and Tolerance of Donor-Derived Mesenchymal Stem Cells in Pediatric Living-Donor Liver Transplantation: The MYSTEP1 Study.

BACKGROUND: Calcineurin inhibitors (CNI) have significantly improved patient and graft survival in pediatric liver transplantation (pLT). However, CNI toxicity leads to significant morbidity. Moreover, CNIs cannot prevent long-term allograft injury. Mesenchymal stem (stromal) cells (MSC) have potent immunomodulatory properties, which may promote allograft tolerance and ameliorate toxicity of high-dose CNI. The MYSTEP1 trial aims to investigate safety and feasibility of donor-derived MSCs in pLT. METHODS/DESIGN: 7 to 10 children undergoing living-donor pLT will be included in this open-label, prospective pilot trial. A dose of 1 × 106 MSCs/kg body weight will be given at two time points: first by intraportal infusion intraoperatively and second by intravenous infusion on postoperative day 2. In addition, participants will receive standard immunosuppressive treatment. Our primary objective is to assess the safety of intraportal and intravenous MSC infusion in pLT recipients. Our secondary objective is to evaluate efficacy of MSC treatment as measured by the individual need for immunosuppression and the incidence of biopsy-proven acute rejection. We will perform detailed immune monitoring to investigate immunomodulatory effects. DISCUSSION: Our study will provide information on the safety of donor-derived MSCs in pediatric living-donor liver transplantation and their effect on immunomodulation and graft survival.

Increasing Morbidity with Extent of Lymphadenectomy for Primary Malignant Melanoma.

BACKGROUND: According to current guidelines, complete lymphadenectomy (LAD) is indicated in melanoma patients with a positive sentinel lymph node. Whereas there is little evidence from randomized trials for a survival benefit of this procedure, its morbidity is not trivial. We aimed to assess clinical associations between risk factors and complications of LAD to guide decision making about this aspect of melanoma management. METHODS AND RESULTS: A cohort of 174 patients who had undergone LAD for primary melanoma was retrospectively analyzed, and multivariable logistic regression models were used to correlate patient risk factors, tumor characteristics, number of excised lymph nodes, and procedural details with the incidence of complications. The overall rate of LAD-associated complications was 41.4%, 33.9% being lymphatic complications. The number of excised lymph nodes was independently associated with development of lymphatic complications (odds ratio 3.90/12.78 if more than 10/20 lymph nodes had been removed, p = 0.01/<0.001, respectively). However, the number of excised lymph nodes had no influence on overall survival using a multivariable Cox proportional hazards regression analysis. CONCLUSIONS: In this retrospective cohort study, an important association was found between the extent of LAD and lymphatic complications. Further studies should evaluate the necessity and extent of aggressive LAD to balance survival benefit with morbidity of LAD procedures.

Concise Review: Mesenchymal Stromal Cell-Based Approaches for the Treatment of Acute Respiratory Distress and Sepsis Syndromes.

Despite extensive research on candidate pharmacological treatments and a significant and increasing prevalence, sepsis syndrome, and acute respiratory distress syndrome (ARDS) remain areas of unmet clinical need. Preclinical studies examining mesenchymal stromal cell (MSCs) based-therapies have provided compelling evidence of potential benefit; however, the precise mechanism by which MSCs exert a therapeutic influence, and whether MSC application is efficacious in humans, remains unknown. Detailed evaluation of the limited number of human trials so far completed is further hampered as a result of variations in trial design and biomarker selection. This review provides a concise summary of current preclinical and clinical knowledge of MSCs as a cell therapy for sepsis syndrome and ARDS. The challenges of modeling such heterogeneous and rapidly progressive disease states are considered and we discuss how lessons from previous studies of pharmacological treatments for sepsis syndrome and ARDS might be used to inform and refine the design of the next generation of MSC clinical trials. Stem Cells Translational Medicine 2017;6:1141-1151.