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The stromal vascular fraction (SVF) is a heterogeneous population of stem/stromal cells isolated from perivascular and extracellular matrix (ECM) of adipose tissue complex (ATC). Administration of SVF holds a strong therapeutic potential for regenerative and wound healing medicine applications aimed at functional restoration of tissues damaged by injuries or chronic diseases. SVF is commonly divided into cellular stromal vascular fraction (cSVF) and tissue stromal vascular fraction (tSVF). Cellular SVF is obtained from ATC by collagenase digestion, incubation/isolation, and pelletized by centrifugation. Enzymatic disaggregation may alter the relevant biological characteristics of adipose tissue, while providing release of complex, multiattachment of cell‐to‐cell and cell‐to‐matrix, effectively eliminating the bioactive ECM and periadventitial attachments. In many countries, the isolation of cellular elements is considered as a “more than minimal” manipulation, and is most often limited to controlled clinical trials and subject to regulatory review. Several alternative, nonenzymatic methods of adipose tissue processing have been developed to obtain via minimal mechanical manipulation an autologous tSVF product intended for delivery, reducing the procedure duration, lowering production costs, decreasing regulatory burden, and shortening the translation into the clinical setting. Ideally, these procedures might allow for the integration of harvesting and processing of adipose tissue for ease of injection, in a single procedure utilizing a nonexpanded cellular product at the point of care, while permitting intraoperative autologous cellular and tissue‐based therapies. Here, we review and discuss the options, advantages, and limitations of the major strategies alternative to enzymatic processing currently developed for minimal manipulation of adipose tissue. Stem Cells Translational Medicine 2019;8:1265&1271 Main strategies for adipose tissue processing.

The development of mesenchymal stem cells (MSCs) as cell‐based drug delivery vectors for numerous clinical indications, including cancer, has significant promise. However, a considerable challenge for effective translation of these approaches is the limited tumor tropism and broad biodistribution observed using conventional MSCs, which raises concerns for toxicity to nontarget peripheral tissues (i.e., the bad). Consequently, there are a variety of synthetic engineering platforms in active development to improve tumor‐selective targeting via increased homing efficiency and/or specificity of drug activation, some of which are already being evaluated clinically (i.e., the good). Unfortunately, the lack of robust quantification and widespread adoption of standardized methodologies with high sensitivity and resolution has made accurate comparisons across studies difficult, which has significantly impeded progress (i.e., the ugly). Herein, we provide a concise review of active and passive MSC homing mechanisms and biodistribution postinfusion; in addition to in vivo cell tracking methodologies and strategies to enhance tumor targeting with a focus on MSC‐based drug delivery strategies for cancer therapy. Stem Cells Translational Medicine 2018;1–13 Mechanical barriers resulting from small vessels in the vascular network are a significant impediment to MSC trafficking via systemic circulation, which severely limits access of exogenously‐introduced MSCs to many target tissues, including tumors, and has implications for MSC‐based drug delivery strategies.

Degenerative musculoskeletal diseases (DMDs), including osteoporosis, osteoarthritis, degenerative disc disease, and sarcopenia, present major challenges in the aging population. Patients with DMDs present with pain, functional decline, and reduced exercise tolerance, which result in long‐term or permanent deficits in their ability to perform daily activities. Current strategies for dealing with this cluster of diseases focus on relieving pain, but they have a limited capacity to repair function or regenerate tissue. Cell‐based therapies have attracted considerable attention in recent years owing to their unique mechanisms of action and remarkable effects on regeneration. In this review, current experimental attempts to use cell‐based therapies for DMDs are highlighted, and the modes of action of different cell types and their derivatives, such as exosomes, are generalized. In addition, the latest findings from state‐of‐the‐art clinical trials are reviewed, approaches to improve the efficiency of cell‐based therapies are summarized, and unresolved questions and potential future research directions for the translation of cell‐based therapies are identified. Degenerative musculoskeletal diseases (DMDs) pose a serious challenge to the elderly. In this review, the latest results from state‐of‐the‐art basic and clinical research are summarized to illustrate the great potential of cell‐based therapies in the treatment of DMDs. Furthermore, this work highlights the unresolved questions for the translation of cell‐based therapies and points out future research directions.

Breakdown of blood-brain barrier, formed mainly by brain microvascular endothelial cells (BMECs), represents the major cause of mortality during early phases of ischemic strokes. Hence, discovery of novel agents that can effectively replace dead or dying endothelial cells to restore blood-brain barrier integrity is of paramount importance in stroke medicine. Although endothelial progenitor cells (EPCs) represent one such agents, their rarity in peripheral blood severely limits their adequate isolation and therapeutic use for acute ischemic stroke which necessitate their ex vivo expansion and generate early EPCs and outgrowth endothelial cells (OECs) as a result. Functional analyses of these cells, in the present study, demonstrated that only OECs endocytosed DiI-labelled acetylated low-density lipoprotein and formed tubules on matrigel, prominent endothelial cell and angiogenesis markers, respectively. Further analyses by flow cytometry demonstrated that OECs expressed specific markers for stemness (CD34), immaturity (CD133) and endothelial cells (CD31) but not for hematopoietic cells (CD45). Like BMECs, OECs established an equally tight in vitro model of human BBB with astrocytes and pericytes, suggesting their capacity to form tight junctions. Ischemic injury mimicked by concurrent deprivation of oxygen and glucose (4 hours) or deprivation of oxygen and glucose followed by reperfusion (20 hours) affected both barrier integrity and function in a similar fashion as evidenced by decreases in transendothelial electrical resistance and increases in paracellular flux, respectively. Wound scratch assays comparing the vasculoreparative capacity of cells revealed that, compared to BMECs, OECs possessed a greater proliferative and directional migratory capacity. In a triple culture model of BBB established with astrocytes, pericytes and BMEC, exogenous addition of OECs effectively repaired the damage induced on endothelial layer in serum-free conditions. Taken together, these data demonstrate that OECs may effectively home to the site of vascular injury and repair the damage to maintain (neuro)vascular homeostasis during or after a cerebral ischemic injury.

Cell therapies for neonatal morbidities are progressing to early phase clinical trials. However, protocols for intravenous (IV) delivery of cell therapies to infants have not been evaluated. It has been assumed the cell dose prescribed is the dose delivered. Early in our clinical trial of human amnion epithelial cells (hAECs), we observed cells settling in the syringe and IV tubing used to deliver the suspension. The effect on dose delivery was unknown. We aimed to quantify this observation and determine an optimal protocol for IV delivery of hAECs to extremely preterm infants. A standard pediatric infusion protocol was modeled in the laboratory. A syringe pump delivered the hAEC suspension over 60 minutes via a pediatric blood transfusion set (200‐μm filter and 2.2 mL IV line). The infusion protocol was varied by agitation methods, IV‐line volumes (0.2‐2.2 mL), albumin concentrations (2% vs 4%), and syringe orientations (horizontal vs vertical) to assess whether these variables influenced the dose delivered. The influence of flow rate (3‐15 mL/h) was assessed after other variables were optimized. The standard infusion protocol delivered 17.6% ± 9% of the intended hAEC dose. Increasing albumin concentration to 4%, positioning the syringe and IV line vertically, and decreasing IV‐line volume to 0.6 mL delivered 99.7% ± 13% of the intended hAEC dose. Flow rate did not affect dose delivery. Cell therapy infusion protocols must be considered. We describe the refinement of a cell infusion protocol that delivers intended cell doses and could form the basis of future neonatal cell delivery protocols. Cell therapy is neonatal medicine's new frontier. While the challenges of translation have been much discussed, we have overlooked a simple yet fundamental hurdle; a protocol that delivers the intended cell dose intravenously to infants. Our existing protocol delivered less than 20% of the intended dose of human amnion epithelial cells. Here, we demonstrate simple measures can optimize cell dose delivery.

Successful isolation of human endometrial stem cells from menstrual blood, namely menstrual blood‐derived endometrial stem cells (MenSCs), has provided enticing alternative seed cells for stem cell‐based therapy. MenSCs are enriched in the self‐regenerative tissue, endometrium, which shed along the periodic menstrual blood and thus their acquisition involves no physical invasiveness. However, the impact of the storage duration of menstrual blood prior to stem cell isolation, the age of the donor, the number of passages on the self‐renewing of MenSCs, the paracrine production of biological factors in MenSCs and expression of adhesion molecules on MenSCs remain elusive. In this study, we confirmed that MenSCs reside in shedding endometrium, and documented that up to 3 days of storage at 4°C has little impact on MenSCs, while the age of the donor and the number of passages are negatively associated with proliferation capacity of MenSCs. Moreover, we found that MenSCs were actually immune‐privileged and projected no risk of tumour formation. Also, we documented a lung‐ and liver‐dominated, spleen‐ and kidney‐involved organic distribution profile of MenSC 3 days after intravenous transfer into mice. At last, we suggested that MenSCs may have potentially therapeutic effects on diseases through paracrine effect and immunomodulation.

Cytotoxic T lymphocyte has been a concern for the etiopathogenesis of alopecia areata (AA), some recent evidence suggests that the regulatory T (T reg ) cell deficiency is also a contributing factor. In the lesional scalp of AA, T reg cells residing in the follicles are impaired, leading to dysregulated local immunity and hair follicle (HF) regeneration disorders. New strategies are emerging to modulate T reg cells’ number and function for autoimmune diseases. There is much interest to boost T reg cells in AA patients to suppress the abnormal autoimmunity of HF and stimulate hair regeneration. With few satisfactory therapeutic regimens available for AA, T reg cell-based therapies could be the way forward. Specifically, CAR-T reg cells and novel formulations of low-dose IL-2 are the alternatives.

This review presents an introduction to the process development challenges of cell therapies and describes some of the tools available to address production issues. A summary is provided of what should be considered to efficiently advance a cellular therapy from the research stage through clinical trials and finally toward commercialization. The development of robust and well‐characterized methods of production of cell therapies has become increasingly important as therapies advance through clinical trials toward approval. A successful cell therapy will be a consistent, safe, and effective cell product, regardless of the cell type or application. Process development strategies can be developed to gain efficiency while maintaining or improving safety and quality profiles. This review presents an introduction to the process development challenges of cell therapies and describes some of the tools available to address production issues. This article will provide a summary of what should be considered to efficiently advance a cellular therapy from the research stage through clinical trials and finally toward commercialization. The identification of the basic questions that affect process development is summarized in the target product profile, and considerations for process optimization are discussed. The goal is to identify potential manufacturing concerns early in the process so they may be addressed effectively and thus increase the probability that a therapy will be successful. Significance The present study contributes to the field of cell therapy by providing a resource for those transitioning a potential therapy from the research stage to clinical and commercial applications. It provides the necessary steps that, when followed, can result in successful therapies from both a clinical and commercial perspective.

Background: Human endometrium with consecutive regeneration capability undergoes monthly hormonal changes for probable implantation, which confirms the presence of the cells in the basalis layer known as stem cell. Objective: Previously, we reported the isolation and culture of the mesenchymal-like cells from human endometrium. In this study, we evaluated the biological and stemness characteristics of these cells. Materials and Methods: The characterization of Yazd human endometrialderived mesenchymal stem/stromal cells (YhEnMSCs) was assessed using immunofluorescence (IF) staining for CD105, VIMENTIN, and FIBRONECTIN as markers and RT-PCR for CD166, CD10, CD105, VIMENTIN, FIBRONECTIN, MHCI, CD14, and MHCII genes. Flow cytometry (FACS) was performed for CD44, CD73, CD90, and CD105 markers. Moreover, the differentiation capacity of the YhEnMSCs to the osteoblast and adipocytes was confirmed by Alizarin Red and Oil Red staining. Results: YhEnMSCs expressed CD105, VIMENTIN, FIBRONECTIN, CD44, CD73, and CD90 markers and CD166, CD10, CD105, VIMENTIN, FIBRONECTIN, and MHCI, but, did not express CD14, MHCII. Conclusion: Our data confirm previous reports by other groups indicating the application of endometrial cells as an available source of MSCs with self-renewal and differentiation capacity. Accordingly, YhEnMSCs can be used as a suitable source for cell-based therapies. Key words: Cell-based therapy, Endometrium, Mesenchymal stem/stromal cells, Regenerative medicine, Stem cells, Uterus.

The ability to identify and stratify patients that will respond to specific therapies has been transformational in a number of disease areas, particularly oncology. It is anticipated that this will also be the case for cell‐based therapies, particularly in complex and heterogeneous diseases such as rheumatoid arthritis (RA). Recently, clinical results with expanded allogenic adipose‐derived mesenchymal stem cells (eASCs) have indicated clinical efficacy in highly refractory RA patients. In this study, we set out to determine if circulating microRNAs (miRNAs) could be identified as potential biomarkers associated with response to eASCs in these RA patients. The miRNA expression profiles of pre‐treatment plasma samples from responder and nonresponder patients were determined using microarrays. Ten miRNAs were identified that were differentially expressed in the responder group as compared to the nonresponder group. To confirm the differential expression of these 10 miRNA biomarkers, they were further assayed by quantitative reverse‐transcriptase polymerase chain reaction (QRT‐PCR). From this analysis, three miRNAs, miR‐26b‐5p, miR‐487b‐3p and miR‐495‐3p, were confirmed as being statistically significantly upregulated in the responder group as compared with the nonresponder group. Receiver operating characteristic analysis confirmed their diagnostic potential. These miRNAs could represent novel candidate stratification biomarkers associated with RA patient response to eASCs and are worthy of further clinical validation. Stem Cells Translational Medicine 2017;6:1202–1206