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The umbilical cord has become an increasingly used source of mesenchymal stromal cells for preclinical and, more recently, clinical studies. Despite the increased activity, several aspects of this cell population have been under‐appreciated. Key issues are that consensus on the anatomical structures within the cord is lacking, and potentially different populations are identified as arising from a single source. To help address these points, we propose a histologically based nomenclature for cord structures and provide an analysis of their developmental origins and composition. Methods of cell isolation from Wharton's jelly are discussed and the immunophenotypic and clonal characteristics of the cells are evaluated. The perivascular origin of the cells is also addressed. Finally, clinical trials with umbilical cord cells are briefly reviewed. Interpreting the outcomes of the many clinical studies that have been undertaken with mesenchymal stromal cells from different tissue sources has been challenging, for many reasons. It is, therefore, particularly important that as umbilical cord cells are increasingly deployed therapeutically, we strive to better understand the derivation and functional characteristics of the cells from this important tissue source. Stem Cells Translational Medicine 2017;6:1620–1630 The human umbilical cord comprises an outer amniotic epithelium surrounding the mucoid connective tissue, Wharton's Jelly, which supports the three umbilical vessels. Wharton's Jelly can be divided into the perivascular compartment, which serves as the tunica adventia of the vessels (and contains the majority of mesenchymal stromal cells), and an intermediate zone that separates the perivascular compartment from the cord lining. Scale Bar = 5 mm.

Bioprinting is a quickly progressing technology, which holds the potential to generate replacement tissues and organs. Stem cells offer several advantages over differentiated cells for use as starting materials, including the potential for autologous tissue and differentiation into multiple cell lines. The three most commonly used stem cells are embryonic, induced pluripotent, and adult stem cells. Cells are combined with various natural and synthetic materials to form bioinks, which are used to fabricate scaffold‐based or scaffold‐free constructs. Computer aided design technology is combined with various bioprinting modalities including droplet‐, extrusion‐, or laser‐based bioprinting to create tissue constructs. Each bioink and modality has its own advantages and disadvantages. Various materials and techniques are combined to maximize the benefits. Researchers have been successful in bioprinting cartilage, bone, cardiac, nervous, liver, and vascular tissues. However, a major limitation to clinical translation is building large‐scale vascularized constructs. Many challenges must be overcome before this technology is used routinely in a clinical setting. Stem Cells Translational Medicine 2017;6:1940–1948 Three major bioprinting modalities are used: droplet‐, extrusion‐, and laser‐based bioprinting. Droplet‐based bioprinting can be divided into three subtypes: inkjet, acoustic, and micro‐valve. Extrusion‐based bioprinting deposition is driven by a pneumatic, mechanical, or solenoid system. Laser‐based bioprinting utilizes an energy absorbing layer and a donor layer. Several tissue types have been successfully bioprinted from stem cells using the various bioprinting modalities, including cartilage, bone, cardiac muscle, neural tissue, liver, and vasculature.

Extreme prematurity is the leading cause of death among children under 5 years of age. Currently, there is no treatment for bronchopulmonary dysplasia (BPD), the most common complication of extreme prematurity. Experimental studies in animal models of BPD suggest that mesenchymal stromal cells (MSCs) are lung protective. To date, no systematic review and meta‐analysis has evaluated the preclinical evidence of this promising therapy. Our protocol was registered with Collaborative Approach to Meta‐Analysis and Review of Animal Data from Experimental Studies prior to searching MEDLINE (1946 to June 1, 2015), Embase (1947 to 2015 Week 22), Pubmed, Web of Science, and conference proceedings (1990 to present) for controlled comparative studies of neonatal animal models that received MSCs or cell free MSC‐derived conditioned media (MSC‐CM). Lung alveolarization was the primary outcome. We used random effects models for data analysis and followed the Preferred Reporting Items for Systematic Reviews and Meta‐Analyses reporting guidelines. We screened 990 citations; 25 met inclusion criteria. All used hyperoxia‐exposed neonatal rodents to model BPD. MSCs significantly improved alveolarization (Standardized mean difference of −1.330, 95% confidence interval [CI −1.724, −0.94, I2 69%]), irrespective of timing of treatment, source, dose, or route of administration. MSCs also significantly ameliorated pulmonary hypertension, lung inflammation, fibrosis, angiogenesis, and apoptosis. Similarly, MSC‐CM significantly improved alveolarization, angiogenesis, and pulmonary artery remodeling. MSCs, tested exclusively in hyperoxic rodent models of BPD, show significant therapeutic benefit. Unclear risk of bias and incomplete reporting in the primary studies highlights nonadherence to reporting standards. Overall, safety and efficacy in other species/large animal models may provide useful information for guiding the design of clinical trials. Stem Cells Translational Medicine 2017;6:2079–2093 MSCs in pre‐clinical bronchopulmonary dysplasia (BPD). In this first‐ever systematic review and meta‐analysis, when tested exclusively in hyperoxic rodent models of BPD, mesenchymal stromal cells significantly improved several outcome measures, although with a high degree of heterogeneity, unclear risk of bias, poor reporting and potential publication bias; underscoring the need to fix methodological flaws by rigorously implementing reporting standards such as Animal Research: Reporting of In Vivo Experiments (ARRIVE) guidelines, thereby ensuring successful clinical translation of this promising therapy.

Gene therapy, cell therapy, and tissue engineering have the potential to revolutionize the treatment of disease and injury. Attaining marketing authorization for such advanced therapy medicinal products (ATMPs) requires a rigorous scientific evaluation by the European Medicines Agency—authorization is only granted if the product can fulfil stringent requirements for quality, safety, and efficacy. However, many ATMPs are being provided to patients under alternative means, such as “hospital exemption” schemes. Holoclar (ex vivo expanded autologous human corneal epithelial cells containing stem cells), a novel treatment for eye burns, is one of the few ATMPs to have been granted marketing authorization and is the first containing stem cells. This review highlights the differences in standards between an authorized and unauthorized medicinal product, and specifically discusses how the manufacture of Holoclar had to be updated to achieve authorization. The result is that patients will have access to a therapy that is manufactured to high commercial standards, and is supported by robust clinical safety and efficacy data. Stem Cells Translational Medicine 2018;7:146–154 The role of clonogenic keratinocytes in generation and renewal of the corneal epithelium. The holoclone differentiation process from highly proliferative self‐renewing holoclones to transiently amplifying cells (meroclones and paraclones). A confocal microscopy image of holoclone stem cells is on the left showing high expression of ΔNp63α, an isoform of the p63 transcription factor.

The popularity of adipose‐derived cell therapy has increased over the last decade, and the number of studies published annually is growing. However, concerns regarding safety in the setting of previous malignancy or the use of allogeneic cells have been raised. We therefore aimed to systematically review all clinical studies using adipose‐derived cell therapy to identify reported adverse events with a special focus on risk of thromboembolic, immunological, and oncological safety concerns. Our systematic search resulted in 70 included studies involving more than 1,400 patients that were treated with adipose‐derived cell therapy. Safety assessment method was not described in 32 of the included studies. For studies involving systemic or cardiac administration, one case of pulmonary thromboembolism and cases of both myocardial and cerebral infarctions were described. In the setting of allogeneic cell therapy studies, where the production of specific antibodies toward donor cells was examined, it was noted that 19%–34% of patients develop antibodies, but the consequence of this is unknown. With regard to oncological safety, only one case of breast cancer recurrence was identified out of 121 patients. Adipose‐derived cell therapy has so far shown a favorable safety profile, but safety assessment description has, in general, been of poor quality, and only adverse events that are looked for will be found. We encourage future studies to maintain a strong focus on the safety profile of cell therapy, so its safeness can be confirmed. Stem Cells Translational Medicine 2017;6:1786–1794 Clinical trials using adipose‐derived cell therapy are increasing and safety concerns in specific settings have been raised. We reviewed the present literature, including more than 1,400 patients receiving cell therapy. Adipose‐derived cell therapy has so far shown a favorable safety profile, but safety assessment description in general has been of poor quality.

Hematopoietic stem cell transplantation (HSCT) is common practice today for life threatening malignant and non‐malignant diseases of the blood and immune systems. Umbilical cord blood (UCB) is rich in hematopoietic stem cells (HSCs) and is an attractive alternative to harvesting HSCs from bone marrow or when mobilized into peripheral blood. One of the most appealing attributes of UCB is that it can be banked for future use and hence provides an off‐the‐shelf solution for patients in urgent need of a transplantation. This has led to the establishment of publicly funded and private UCB banks, as seen by the rapid growth of the UCB industry in the early part of this century. However, from about 2010, the release of UCB units for treatment purposes plateaued and started to decrease year‐on‐year from 2013 to 2016. Our interest has been to investigate the factors contributing to these changes. Key drivers influencing the UCB industry include the emergence of haploidentical HSCT and the increasing use of UCB units for regenerative medicine purposes. Further influencing this dynamic is the high cost associated with UCB transplantation, the economic impact of sustaining public bank operations and an active private UCB banking sector. We foresee that these factors will continue in a tug‐of‐war fashion to shape and finally determine the fate of the UCB industry. Stem Cells Translational Medicine 2018 Stem Cells Translational Medicine 2018;7:643–650 Evolution and factors influencing the future growth of the umbilical cord (UCB) industry. Positive influencers will allow for a plateau or rise in UCB usage, while negative influencers will result in a further decline.

Tracheal replacement for the treatment of end‐stage airway disease remains an elusive goal. The use of tissue‐engineered tracheae in compassionate use cases suggests that such an approach is a viable option. Here, a stem cell‐seeded, decellularized tissue‐engineered tracheal graft was used on a compassionate basis for a girl with critical tracheal stenosis after conventional reconstructive techniques failed. The graft represents the first cell‐seeded tracheal graft manufactured to full good manufacturing practice (GMP) standards. We report important preclinical and clinical data from the case, which ended in the death of the recipient. Early results were encouraging, but an acute event, hypothesized to be an intrathoracic bleed, caused sudden airway obstruction 3 weeks post‐transplantation, resulting in her death. We detail the clinical events and identify areas of priority to improve future grafts. In particular, we advocate the use of stents during the first few months post‐implantation. The negative outcome of this case highlights the inherent difficulties in clinical translation where preclinical in vivo models cannot replicate complex clinical scenarios that are encountered. The practical difficulties in delivering GMP grafts underscore the need to refine protocols for phase I clinical trials. Stem Cells Translational Medicine 2017;6:1458–1464 Here, a stem cell‐seeded, decellularized tissue‐engineered tracheal graft was used on a compassionate basis for a girl with critical tracheal stenosis after conventional reconstructive techniques failed. We report a compassionate use case of tracheal tissue engineering using a cell‐seeded, decellularized donor trachea. The teenage recipient had critical stenosis after conventional reconstructive techniques had failed. The case involved application of full good manufacturing practice standards to create a manufactured advanced medical product for transplantation.

The possibility of using adipose tissue-derived stromal cells (ATSC) as alternatives to bone marrow-derived stromal cells (BMSC) for bone repair has garnered interest due to the accessibility, high cell yield, and rapid in vitro expansion of ATSC. For clinical relevance, their bone forming potential in comparison to BMSC must be proven. Distinct differences between ATSC and BMSC have been observed in vitro and comparison of osteogenic potential in vivo is not clear to date. The aim of the current study was to compare the osteogenesis of human xenofree-expanded ATSC and BMSC in vitro and in an ectopic nude mouse model of bone formation. Human MSC were implanted with biphasic calcium phosphate biomaterials in subcutis pockets for 8 weeks. Implant groups were: BMSC, ATSC, BMSC and ATSC mixed together in different ratios, as well as MSC primed with either osteogenic supplements (250 lM ascorbic acid, 10 mM b-glycerolphosphate, and 10 nM dexametha-sone) or 50 ng/ml recombinant bone morphogenetic protein 4 prior to implantation. In vitro results show osteogenic gene expression and differentiation potentials of ATSC. Despite this, ATSC failed to form ectopic bone in vivo, in stark contrast to BMSC, although osteogenic priming did impart minor osteogenesis to ATSC. Neovascularization was enhanced by ATSC compared with BMSC; however, less ATSC engrafted into the implant compared with BMSC. Therefore, in the content of bone regen-eration, the advantages of ATSC over BMSC including enhanced angiogenesis, may be negated by their lack of osteogenesis and prerequisite for osteogenic differentiation prior to transplantation.

Regenerative medicine is a new branch of medicine based on tissue engineering technology. This rapidly developing field of science offers revolutionary treatment strategy aimed at urinary bladder regeneration. Despite many promising announcements of experimental urinary bladder reconstruction, there has been a lack in commercialization of therapies based on current investigations. This is due to numerous obstacles that are slowly being identified and precisely overcome. The goal of this review is to present the current status of research on urinary bladder regeneration and highlight further challenges that need to be gradually addressed. We put an emphasis on expectations of urologists that are awaiting tissue engineering based solutions in clinical practice. This review also presents a detailed characteristic of obstacles on the road to successful urinary bladder regeneration from urological clinician perspective. A defined interdisciplinary approach might help to accelerate planning transitional research tissue engineering focused on urinary tracts. Stem Cells Translational Medicine 2017;6:2033–2043 Indications for cystectomy with subsequently performed urine diversion comprise malignant and nonmalignant conditions. Invasive bladder cancer is the most common of them. Tissue engineering strategies included noncellular (A) and cellular (B) grafts, developed for bladder replacement.

Several alternative techniques exist to reconstruct skull defects. The complication rate of the cranioplasty procedure is high and the search for optimal materials and techniques continues. To report long‐term results of patients who have received a cranioplasty using autologous adipose‐derived stem cells (ASCs) seeded on beta‐tricalcium phosphate (betaTCP) granules. Between 10/2008 and 3/2010, five cranioplasties were performed (four females, one male; average age 62.0 years) using ASCs, betaTCP granules and titanium or resorbable meshes. The average defect size was 8.1 × 6.7 cm2. Patients were followed both clinically and radiologically. The initial results were promising, with no serious complications. Nevertheless, in the long‐term follow‐up, three of the five patients were re‐operated due to graft related problems. Two patients showed marked resorption of the graft, which led to revision surgery. One patient developed a late infection (7.3 years post‐operative) that required revision surgery and removal of the graft. One patient had a successfully ossified graft, but was re‐operated due to recurrence of the meningioma 2.2 years post‐operatively. One patient had an uneventful clinical follow‐up, and the cosmetic result is satisfactory, even though skull x‐rays show hypodensity in the borders of the graft. Albeit no serious adverse events occurred, the 6‐year follow‐up results of the five cases are unsatisfactory. The clinical results are not superior to results achieved by conventional cranial repair methods. The use of stem cells in combination with betaTCP granules and supporting meshes in cranial defect reconstruction need to be studied further before continuing with clinical trials. Stem Cells Translational Medicine 2017;6:1576–1582 Reformatted CT image 13 months after reconstruction of the skull with autologous adipose stem cells, beta‐tricalcium phosphate granules and supporting mesh.