Targeted cell delivery of mesenchymal stem cell therapy for cardiovascular disease applications: a review of preclinical advancements

Cardiovascular diseases (CVD) continue to be the leading cause of morbidity and mortality globally and claim the lives of over 17 million people annually. Current management of CVD includes risk factor modification and preventative strategies including dietary and lifestyle changes, smoking cessation, medical management of hypertension and cholesterol lipid levels, and even surgical revascularization procedures if needed. Although these strategies have shown therapeutic efficacy in reducing major adverse cardiovascular events such as heart attack, stroke, symptoms of chronic limb-threatening ischemia (CLTI), and major limb amputation significant compliance by patients and caregivers is required and off-target effects from systemic medications can still result in organ dysfunction. Stem cell therapy holds major potential for CVD applications but is limited by the low quantities of cells that are able to traffic to and engraft at diseased tissue sites. New preclinical investigations have been undertaken to modify mesenchymal stem cells (MSCs) to achieve targeted cell delivery after systemic administration. Although previous reviews have focused broadly on the modification of MSCs for numerous local or intracoronary administration strategies, here we review recent preclinical advances related to overcoming challenges imposed by the high velocity and dynamic flow of the circulatory system to specifically deliver MSCs to ischemic cardiac and peripheral tissue sites. Many of these technologies can also be applied for the targeted delivery of other types of therapeutic cells for treating various diseases

Robust estimation of bacterial cell count from optical density

Optical density (OD) is widely used to estimate the density of cells in liquid culture, but cannot be compared between instruments without a standardized calibration protocol and is challenging to relate to actual cell count. We address this with an interlaboratory study comparing three simple, low-cost, and highly accessible OD calibration protocols across 244 laboratories, applied to eight strains of constitutive GFP-expressing E. coli. Based on our results, we recommend calibrating OD to estimated cell count using serial dilution of silica microspheres, which produces highly precise calibration (95.5% of residuals <1.2-fold), is easily assessed for quality control, also assesses instrument effective linear range, and can be combined with fluorescence calibration to obtain units of Molecules of Equivalent Fluorescein (MEFL) per cell, allowing direct comparison and data fusion with flow cytometry measurements: in our study, fluorescence per cell measurements showed only a 1.07-fold mean difference between plate reader and flow cytometry data

Pulmonary metastasectomy in pediatric patients: a narrative review

Background and Objective: Metastatic pulmonary disease associated with primary solid tumors is associated with poor prognosis in the pediatric population. Indications for pulmonary metastasectomy in childhood is largely dependent on primary tumor histology; however, its role in the multimodal treatment of different tumors remains controversial. While surgical management traditionally involves open resection, utilization of video-assisted thoracoscopic surgery (VATS) has increased in recent years. Here, we review oncologic subtypes commonly treated by pulmonary metastasectomy and operative approaches for metasectomy as well as their associated outcomes.Methods: A comprehensive review of the literature published from January, 1990 to February, 2023 was performed via independent searches of the publicly available databases the National Institute of Health National Library of Medicine PubMed and MEDLINE for indexed and published articles.Key Content and Findings: More recent studies have been undertaken to describe the indications and outcomes of pulmonary metastasectomy in pediatric patients with specific tumor pathologies. VATS approach is associated with fewer complications and shorter length of stay (LOS) compared to open thoracotomy in children.Conclusions: Significant advances have been made in evaluating the role of pulmonary metastasectomy for pediatric specific tumors as part of a multimodal treatment approach. Although the use of VATS for pulmonary metastasectomy has increased, open resection remains the standard approach for pediatric patients. While VATS is associated with short-term clinical benefits, further studies are needed to evaluate its long-term outcomes for pediatric malignancies

Methods and Limitations of Augmenting Mesenchymal Stem Cells for Therapeutic Applications

Significance: Given their capacity for self-renewal, multilineage differentiation, and immunomodulatory potential, mesenchymal stem cells (MSCs) represent a promising modality of clinical therapy for both regenerative medicine and immune diseases. In this study, we review the key approaches and popular methods utilized to boost potency and modify functions of MSCs for clinical purposes as well as their associated limitations.Recent Advances: Several major domains of cell modification strategies are currently employed by investigators to overcome these deficits and augment the therapeutic potential of MSCs. Priming MSCs with soluble factors or pharmacologic agents as well as manipulating oxygen availability in culture have been demonstrated to be effective biochemical methods to augment MSC potential. Distinct genetic and epigenetic methods have emerged in recent years to modify the genetic expression of target proteins and factors thereby modulating MSCs capacity for differentiation, migration, and proliferation. Physical methods utilizing three-dimensional culture methods and alternative cell delivery systems and scaffolds can be used to recapitulate the native MSC niche and augment their engraftment and viability for in vivo models.Critical Issues: Unmodified MSCs have demonstrated only modest benefits in many preclinical and clinical studies due to issues with cell engraftment, viability, heterogeneity, and immunocompatibility between donor and recipient. Furthermore, unmodified MSCs can have low inherent therapeutic potential for which intensive research over the past few decades has been dedicated to improving cell functionality and potency

Targeted cell delivery of mesenchymal stem cell therapy for cardiovascular disease applications: a review of preclinical advancements

Cardiovascular diseases (CVD) continue to be the leading cause of morbidity and mortality globally and claim the lives of over 17 million people annually. Current management of CVD includes risk factor modification and preventative strategies including dietary and lifestyle changes, smoking cessation, medical management of hypertension and cholesterol lipid levels, and even surgical revascularization procedures if needed. Although these strategies have shown therapeutic efficacy in reducing major adverse cardiovascular events such as heart attack, stroke, symptoms of chronic limb-threatening ischemia (CLTI), and major limb amputation significant compliance by patients and caregivers is required and off-target effects from systemic medications can still result in organ dysfunction. Stem cell therapy holds major potential for CVD applications but is limited by the low quantities of cells that are able to traffic to and engraft at diseased tissue sites. New preclinical investigations have been undertaken to modify mesenchymal stem cells (MSCs) to achieve targeted cell delivery after systemic administration. Although previous reviews have focused broadly on the modification of MSCs for numerous local or intracoronary administration strategies, here we review recent preclinical advances related to overcoming challenges imposed by the high velocity and dynamic flow of the circulatory system to specifically deliver MSCs to ischemic cardiac and peripheral tissue sites. Many of these technologies can also be applied for the targeted delivery of other types of therapeutic cells for treating various diseases

Small Intestinal Perforation Secondary to Necrotizing Enteritis—An Under-Recognized Complication of Crohn’s Disease

Small bowel perforation is an uncommon but severe event in the natural history of Crohn’s disease with fewer than 100 cases reported. We review Crohn’s disease cases with necrotizing enteritis and share a case of a 26-year-old female who presented with a recurrent episode of small intestinal perforation. A PubMed literature review of case reports and series was conducted using keywords and combinations of “Crohn’s disease,” “small intestine perforation,” “small bowel perforation,” “free perforation,” “regional enteritis,” and “necrotizing enteritis.” Data extracted included demographic data, pre- or postoperative steroid administration, medical or surgical management, and case fatality. Nineteen reports from 1935 to 2021 qualified for inclusion. There were 43 patients: 20 males and 23 females with a mean age of 36 ± 15 years old. 75 total perforations were described: 56 ileal (74.6%), 15 jejunal (20.0%), 2 cecal (2.7%), and 1 small intestine non-specified (2.7%). 38 of 43 patients were managed surgically by primary repair (11), ostomy creation (21), or an anastomosis (11). Of 11 case fatalities, medical management alone was associated with higher mortality (5/5; 100% mortality) compared to those treated surgically (6/38; 15.8% mortality; P < .001). Patient sex, disease history, acute abdomen, and pre- or postoperative steroid use did not significantly correlate with mortality. Jejunal perforation was significantly ( P = .028) associated with event mortality while ileal was not ( P = .45). Although uncommon, necrotizing enteritis should be considered in Crohn’s patients who present with small intestinal perforation. These cases often require urgent surgical intervention and may progress to fulminant sepsis and fatality if not adequately treated

Mesenchymal stem cell-based therapy for non-healing wounds due to chronic limb-threatening ischemia: A review of preclinical and clinical studies

Progressive peripheral arterial disease (PAD) can result in chronic limb-threatening ischemia (CLTI) characterized by clinical complications including rest pain, gangrene and tissue loss. These complications can propagate even more precipitously in the setting of common concomitant diseases in patients with CLTI such as diabetes mellitus (DM). CLTI ulcers are cutaneous, non-healing wounds that persist due to the reduced perfusion and dysfunctional neovascularization associated with severe PAD. Existing therapies for CLTI are primarily limited to anatomic revascularization and medical management of contributing factors such as atherosclerosis and glycemic control. However, many patients fail these treatment strategies and are considered "no-option," thereby requiring extremity amputation, particularly if non-healing wounds become infected or fulminant gangrene develops. Given the high economic burden imposed on patients, decreased quality of life, and poor survival of no-option CLTI patients, regenerative therapies aimed at neovascularization to improve wound healing and limb salvage hold significant promise. Cell-based therapy, specifically utilizing mesenchymal stem/stromal cells (MSCs), is one such regenerative strategy to stimulate therapeutic angiogenesis and tissue regeneration. Although previous reviews have focused primarily on revascularization outcomes after MSC treatments of CLTI with less attention given to their effects on wound healing, here we review advances in pre-clinical and clinical studies related to specific effects of MSC-based therapeutics upon ischemic non-healing wounds associated with CLTI

Middle mediastinal cavernous hemangioma: a case report of clinical, pathologic and radiologic features

Benign vascular tumors of the mediastinum are rare, representing only 0.5% of all mediastinal masses. Given their rare presentation, they are infrequently considered in the workup of a middle mediastinal mass. We present a unique case describing the clinical, imaging and pathologic characteristics of a middle mediastinal cavernous hemangioma which was initially misdiagnosed as a bronchogenic cyst and ultimately required surgical resection with the use of veno-venous extracorporeal membrane oxygenation