Publications

Sepsis is one of the leading causes of morbidity and mortality in the United States and Worldwide despite advances in quick recognition and early antibiotics, fluids, and vasopressors. Mesenchymal stem/stromal cells (MSCs) have gained attention as a biologic therapy given their unique anti-inflammatory, immunomodulatory, and anti-bacterial characteristics. MSCs have had success in treating a range of diseases, however limited clinical trials exist specifically for MSC use in sepsis. This article reviews the properties of MSCs that make them favorable for treating sepsis, as well as the current state of clinical trials. All clinical trials presented here demonstrated MSC safety, with a mixture of efficacy results and a heterogeneity of trial methods. Ultimately, MSCs are a promising novel therapeutic for sepsis, however a consensus in cell source, dosage, preparation, and delivery needs to be further investigated for MSCs to transition from bench to bedside and become a true therapeutic for sepsis.

BACKGROUND: Emergency Medicine (EM) physicians routinely treat breastfeeding patients. Physicians frequently recommend pumping and dumping milk for perceived safety risks. We hypothesized that the majority of the most commonly ordered medications in the emergency department (ED) are safe for breastfeeding patients. Accordingly, we performed a comprehensive safety analysis of the commonly ordered medications and provided an algorithm for EM physicians to utilize when treating breastfeeding patient in the ED.

METHODS: We investigated the 90 most administered medications to female patients between the ages of 15 to 50 for common ED chief complaints at a tertiary care academic medical center from January 2018 to December 2022. A total of 145,960 doses were analyzed. We subsequently searched LactMed®, InfantRisk Application, and Pubmed® for all safety information on these medications and divided them by categories. Ultimately, we proposed a treatment algorithm for breastfeeding patients in the ED.

RESULTS: Analgesics were the most commonly ordered medications in the ED, and importantly analgesics ranging from ibuprofen to morphine are safe in limited doses in the ED setting. Antibiotics and antifungals pose limited restrictions. All systems-based medications have a variety of safe options available. Lastly, supplements and electrolytes are safe.

CONCLUSION: The majority of medications utilized in the acute setting are compatible with breastfeeding. There should be limited circumstances to advise pumping and dumping in the ED.

Introduction: Ornithine Transcarbamylase (OTC) deficiency-an X-linked disorder-is the most common urea cycle defect in infancy and often presents with elevated ammonia.

Case presentation: A 2-month-old with a normal newborn screen presented with feeding difficulties. The patient was incorrectly diagnosed with gastroesophageal reflux, which at 4 months progressed to recurrent vomiting. At 5 months he developed status epilepticus, was found to have an ammonia level >500 micromol/L, and genetic testing revealed OTC deficiency.

Conclusion: Despite a normal newborn screen, unusual infant presentations need to be approached with a broad differential in order to prevent deleterious outcomes.

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INTRODUCTION: Accumulating evidence supports the use of mesenchymal stem/stromal cells (MSCs), particularly bone marrow derived, as a safe and promising biologic therapy for promoting tissue repair and regeneration in various chronic diseases and disorders. Despite growing evidence that MSCs are potent anti-inflammatory mediators that can provide substantial benefits in acute organ injury, there are limited clinical trials utilizing MSCs in acute care settings, such as in the emergency department (ED) or intensive care unit (ICU).

OBJECTIVE: This article reviews the current state of MSC-based therapeutics and further explores the untapped potential role to treat various acute, life-threating injuries in the ED and ICU.

DISCUSSION: All clinical trials using MSCs in acute myocardial infarction (AMI), acute respiratory distress syndrome (ARDS), sepsis and acute kidney injury (AKI) demonstrated safety. While some also demonstrate clinical efficacy, efficacy data is inconsistent, with some studies limited by sample size, cell integrity and different dosages, necessitating further studies.

CONCLUSION: MSCs are potentially promising novel biologic therapeutics for clinical application in AMI, ARDS, sepsis, AKI and COVID-19 that have demonstrated safety in all clinical trials. More rigorous clinical trials are necessary and warranted to determine the efficacy of MSCs as a novel therapeutic in an acute setting, such as the ED.

Mesenchymal stem cell (MSC) administration is a novel and promising therapeutic approach for Alzheimer's disease (AD). Focusing on an intervention easily translatable into clinical practice, we administered allogeneic bone marrow-derived MSCs intravenously in a mouse model of AD (3xTg-AD). We systematically evaluated the effects of a single-dose and multiple-doses of MSCs in young and old mice (5 or 10 months old), comparing the short-term and long-term effects after 1, 2, or 7 months of treatment. A single dose of MSCs in young mice attenuated neuroinflammation 1 and 7 months after injection, whereas multiple-doses did not show any effect. Multiple-doses of MSCs (administered at 5 to 12 mo, or 10 to 12 mo) reduced the β-secretase cleavage of the amyloid precursor protein, although levels of Aβ-42 did not change. Most interestingly, multiple doses of MSCs affected tau hyperphosphorylation. MSCs administered in young mice for 7 months decreased the pathological tau phosphorylation at T205, S214, and T231. MSCs administered in old mice for 2 months decreased tau phosphorylation at S396. Our findings show how different timing and frequency of MSC injections can affect and modulate several aspects of the AD-like neuropathology in the 3xTg-AD mouse model, strengthening the concept of fine-tuning MSC therapy for Alzheimer's disease.

AIMS: Sex differences impact the occurrence, presentation, prognosis, and response to therapy in heart disease. Particularly, the phenotypic presentation of patients with non-ischaemic dilated cardiomyopathy (NIDCM) differs between men and women. However, whether the response to mesenchymal stem cell (MSC) therapy is influenced by sex remains unknown. We hypothesize that males and females with NIDCM respond similarly to MSC therapy.

METHODS AND RESULTS: Male (n = 24) and female (n = 10) patients from the POSEIDON-DCM trial who received MSCs via transendocardial injections were evaluated over 12 months. Endothelial function was measured at baseline and 3 months post-transendocardial stem cell injection (TESI). At baseline, ejection fraction (EF) was lower (P = 0.004) and end-diastolic volume (EDV; P = 0.0002) and end-systolic volume (ESV; P = 0.0002) were higher in males vs. females. In contrast, baseline demographic characteristics, Minnesota Living with Heart Failure Questionnaire (MLHFQ), and 6-min walk test (6MWT) were similar between groups. EF improved in males by 6.2 units (P = 0.04) and in females by 8.6 units (P = 0.04; males vs. females, P = 0.57). EDV and ESV were unchanged over time. The MLHFQ score, New York Heart Association (NYHA) class, endothelial progenitor cell-colony forming units, and serum tumour necrosis factor alpha improved similarly in both groups.

CONCLUSION: Despite major differences in phenotypic presentation of NIDCM in males and females, this study is the first of its kind to demonstrate that MSC therapy improves a variety of parameters in NIDCM irrespective of patient sex. These findings have important clinical and pathophysiologic implications regarding the impact of sex on responses to cell-based therapy for NIDCM.

BACKGROUND: Despite limited human data, there is a growing interest in the use of stem cell therapy (SCT) for erectile dysfunction (ED).

AIM: To determine the effect of transendocardial stem cell injection on erectile function on men with cardiomyopathy and ED.

METHODS: We used International Index of Erectile Function (IIEF) scores collected from men enrolled in 3 separate randomized controlled trials: Comparison of Allogeneic vs Autologous Bone Marrow-Derived Mesenchymal Stem Cells Delivered by Transendocardial Injection in Patients With Ischemic Cardiomyopathy (POSEIDON), Transendocardial Mesenchymal Stem Cells and Mononuclear Bone Marrow Cells for Ischemic Cardiomyopathy (TAC-HFT), and Dose Comparison Study of Allogeneic Mesenchymal Stem Cells in Patients With Ischemic Cardiomyopathy (TRIDENT). These trials recruited patients with ischemic cardiomyopathy and ejection fraction less than 50%. Inclusion and exclusion criteria were identical in all 3 trials. The primary intervention in these trials included transendocardial stem cell injection of stem cells or placebo via cardiac catheterization. The follow-up period was 1 year. IIEF data were collected at baseline and at multiple time points in each trial.

OUTCOMES: We investigated erectile function over time based on cell dose, cell source (autologous vs allogenic), cell type (mesenchymal stem cells vs bone marrow mononuclear cells), and comparing men who received SCT with those who received placebo.

RESULTS: A total of 36 men were identified with complete IIEF data. 8 men received placebo injection, and 28 received SCT. The median age was 66.5 years. Comorbidities were similar among all men. Analysis was performed on men with ED, defined by an IIEF-EF score of 24 or less. In the placebo and all-comer SCT group, the median IIEF-EF score was 5 [1-8] and 5 [1-15] at baseline and was 3.5 [3-5.8] and 7 [1-18] at 12 months (P > .05). When analyzed by cell dose, the IIEF-EF score in men who received 200 million cells increased significantly over 12 months (14 [4-23] to 20 [15-24.5], P = .014.) Similarly, an autologous cell source resulted in a similar increase from baseline to 12 months (14 [3.8-23.3] to 20 [12-22], P = .030).

CLINICAL IMPLICATIONS: Erectile function may improve after systemic delivery of SCT in men with ischemic cardiomyopathy and at least mild ED.

STRENGTHS & LIMITATIONS: This post hoc analysis is the first to investigate the effect of SCT on erectile function using randomized, placebo-controlled data. Weaknesses include that ED was not a primary end point, and men were not originally recruited based on erectile function.

CONCLUSION: Future trials on systemic delivery of SCT for ED should focus on high cell dose and autologous cell source, as these seem to provide the best response in men with at least mild ED. Ory J, Saltzman RG, Blachman-Braun R, et al. The Effect of Transendocardial Stem Cell Injection on Erectile Function in Men With Cardiomyopathy: Results From the TRIDENT, POSEIDON, and TAC-HFT Trials. J Sex Med 2020;17:695-701.

Endothelial dysfunction is characterized by nitric oxide dysregulation and an altered redox state. Oxidative stress and inflammatory markers prevail, thus promoting atherogenesis and hypertension, important risk factors for the development and progression of heart failure. There has been a reemerging interest in the role that endothelial dysfunction plays in the failing circulation. Accordingly, patients with heart failure are being clinically assessed for endothelial dysfunction via various methods, including flow-mediated vasodilation, peripheral arterial tonometry, quantification of circulating endothelial progenitor cells, and early and late endothelial progenitor cell outgrowth measurements. Although the mechanisms underlying endothelial dysfunction are intimately related to cardiovascular disease and heart failure, it remains unclear whether targeting endothelial dysfunction is a feasible strategy for ameliorating heart failure progression. This review focuses on the pathophysiology of endothelial dysfunction, the mechanisms linking endothelial dysfunction and heart failure, and the various diagnostic methods currently used to measure endothelial function, ultimately highlighting the therapeutic implications of targeting endothelial dysfunction for the treatment of heart failure.

BACKGROUND: Endothelial dysfunction contributes to the pathophysiology of dilated cardiomyopathy (DCM). Allogeneic but not autologous mesenchymal stem cells (MSCs) improve endothelial function in DCM patients. We hypothesized that these effects are modulated by release of stromal derived factor-1α (SDF-1α).

METHODS: Plasma TNFα and endothelial progenitor cell-colony forming units (EPC-CFUs) were assessed at baseline and 3-months post-injection in a subset of POSEIDON-DCM patients that received autologous (n = 11) or allogeneic (n = 10) MSCs. SDF-1α secretion by MSCs, endothelial cell (EC) TNFα mRNA expression, and levels of reactive oxygen species (ROS) in response to SDF-1α were measured in vitro.

RESULTS: As previously shown, DCM patients (n = 21) had reduced EPC-CFUs at baseline (3 ± 3), which were restored to normal by allogeneic MSCs 3-months post-treatment (Δ10 ± 4). DCM patients had elevated baseline plasma TNFα (n = 15, 22 ± 9.4 pg/mL). Allogeneic MSCs (n = 8) decreased, and autologous MSCs (n = 7) increased, plasma TNFα (-7.1 ± 3.1 vs. 22.2 ± 17.1 pg/mL, respectively; P = 0.0005). In culture, autologous MSCs (n = 11) secreted higher levels of SDF-1α than allogeneic MSCs (n = 6) [76.0 (63.7, 100.9) vs. 22.8 (7.2, 43.5) pg/mL, P = 0.0002]. SDF-1α and plasma TNFα negatively correlated with EPC-CFUs in both treatment groups (R = -0.7, P = 0.0004). ECs treated with 20 ng SDF-1α expressed lower levels of TNFα mRNA than cells treated with 100 ng (0.7 ± 0.2 vs. 2.1 ± 0.3, P = 0.0008). SDF-1α at low but not high concentration inhibited the generation of ROS.

CONCLUSION: MSC secretion of SDF-1α inversely correlates with EPC-CFU production in DCM patients and therefore may be a modulator of MSC therapeutic effect in this clinical setting.

CLINICAL TRIAL REGISTRATION: https://clinicaltrials.gov/ct2/show/NCT01392625, identifier NCT01392625.