In this review we present current evidence on the possibility of umbilical cord tissue cryopreservation for subsequent clinical use. Protocols for obtaining umbilical cord-derived vessels, Wharton's jelly-based grafts, multipotent stromal cells, and other biomedical products from cryopreserved umbilical cords are highlighted, and their prospective clinical applications are discussed. Examination of recent literature indicates we should expect high demand for cryopreservation of umbilical cord tissues in the near future.

Interest gaps between public and private umbilical cord blood banks have led to the introduction of hybrid banking options. Hybrid models combine features of private and public banks as well as interests of parents, children and of patients, in order to find an optimized solution. While several different models of hybrid banks exist, there is a lack of literature about this novel model of cord blood stem cell banking. Therefore, the aim of this literature review is to assess different options of umbilical cord blood banking and whether hybrid banking could be a valuable alternative to the existing public and private cord blood banking models.

Stillbirth is a sudden and painful event for parents and obstetrical specialists as well. It is, therefore, of greatest importance to be able to give answers for the cause in order to plan a subsequent pregnancy. The aim of this retrospective study is to estimate the placental and umbilical cord cause of intrauterine death in relation to different gestational ages. The study took place on the Medical Birth Registry of Aretaieio Hospital, National and Kapodistrian University, Athens, Greece. We include a total of 19,283 pregnancies from 1998 to 2012. In this study period, 431 embryonic deaths occurred. The clinical history was documented on admission at delivery. Conditions thought to be associated with the intrauterine fetal death were recorded. Gestational age was calculated from the last menstrual period as well as with the three-trimester system. The autopsy, placenta and umbilical cord examination were performed by the same laboratory of pathology in Aretaieio University Hospital. We found that the majority of stillbirths occurred in the second trimester. We examined placenta and umbilical cord in all cases. The most frequent histologic abnormalities were those indicated placental vascular insufficiency. As far as the umbilical cord is concerned we found that the inflammatory disorder was the most common in antepartum deaths. A single umbilical artery was significantly related to gestational diabetes and congenital embryonic anomalies. Finally, our results showed steady declines in antepartum deaths during 1998-2012. As a result, we reached the conclusion that in order to reduce the fetal death rate, we have to insist on the autopsy of the placenta and umbilical cord in order to gain the appropriate information in counseling the parents.

Corneal integrity is critical for vision. Corneal wounds frequently heal with scarring that impairs vision. Recently, human umbilical cord mesenchymal stem cells (cord stem cells) have been investigated for tissue engineering and therapy due to their availability and differentiation potential. In this study, we used cord stem cells in a 3-dimensional (3D) stroma-like model to observe extracellular matrix organization, with human corneal fibroblasts acting as a control. For 4 weeks, the cells were stimulated with a stable Vitamin C (VitC) derivative ±TGF-b1. After 4 weeks, the mean thickness of the constructs was ~30 mm; however, cord stem cell constructs had 50% less cells per unit volume, indicating the formation of a dense matrix. We found minimal change in decorin and lumican mRNA, and a significant increase in perlecan mRNA in the presence of TGF-b1. Keratocan on the other hand decreased with TGF-b1 in both cell lineages. With both cell types, the constructs possessed aligned collagen fibrils and associated glycosaminoglycans. Fibril diameters did not change with TGF-b1 stimulation or cell lineage; however, highly sulfated glycosaminoglycans associated with the collagen fibrils significantly increased with TGF-b1. Overall, we have shown that cord stem cells can secrete their own extracellular matrix and promote the deposition and sulfation of various proteoglycans. Furthermore, these cells are at least comparable to commonly used corneal fibroblasts and present an alternative for the 3D in vitro tissue engineered model.

Unfortunately, many patients referred for hematopoietic cell transplant will not have a fully matched related donor, and finding matched unrelated donors through the registry may be difficult, especially if the recipient is not of Northern European descent [N Engl J Med 2014;371:339-348]. Umbilical cord blood (UCB) has been an available graft source for hematopoietic cell transplant for more than 30 years, since the first UCB transplant was performed in the late 1980s [N Engl J Med 1989;321:1174-1178]. UCB is readily available, has low immunogenicity, and does not require as strict of human leukocyte antigen (HLA) matching compared to other graft sources [N Engl J Med 2004;351:2265-2275]. According to data from the Center for International Blood and Marrow Transplant Research (CIBMTR), an estimated 500 patients in the US will have received a UCB transplant in 2018. Since 2014, haploidentical transplants have surpassed UCB transplants performed in the United States (CIBMTR Summary Slides, 2018, available at https://www.cibmtr.org). Increased use of haploidentical transplants has brought to light concerns about UCB transplants, including delayed engraftment and graft failure, increased nonrelapse mortality, increased infection risk, and UCB acquisition costs [Lancet Oncol 2010;11:653-660; Biol Blood Marrow Transplant 2019;1456-1464]. These concerns will need to be addressed for UCB to remain a viable option as a graft source for hematopoietic cell transplant. Other promising therapeutic benefits for UCB, in addition to hematopoietic cell transplant, is its use in regenerative medicine and immune modulation, which is currently being evaluated in ongoing clinical trials.

Although the characteristics of SC, including UC-derived cells, are a dramatically discussed issue, this review will focus particularly on some controversial issues regarding clinical utility of cells isolated from UC tissue. UC-derived cells have several advantages compared to other types and sources of stem cells. The impact of UC topography on cell characteristics is briefly discussed. The necessity to adapt existing methods of cell isolation and culturing to GMP conditions is mentioned, as well as possible cryopreservation of this material. Light is shed on some future perspectives for UC-derived cells.

Umbilical cord blood transplantation (UCBT) has been performed in the clinic for over 30 years. The biological and immunological characteristics of umbilical cord blood (UCB) have been re-recognized in recent years. UCB, previously considered medical waste, is rich in hematopoietic stem cells (HSCs), which are naïve and more energetic and more easily expanded than other stem cells. UCB has been identified as a reliable source of HSCs for allogeneic hematopoietic stem cell transplantation (allo-HSCT). UCBT has several advantages over other methods, including no harm to mothers and donors, an off-the-shelf product for urgent use, less stringent HLA match, lower incidence and severity of chronic graft-vs-host disease (GVHD), and probably a stronger graft-vs-leukemia effect, especially for minimal residual disease-positive patients before transplant. Recent studies have shown that the outcome of UCBT has been improved and is comparable to other types of allo-HSCT. Currently, UCBT is widely used in malignant, nonmalignant, hematological, congenital and metabolic diseases. The number of UCB banks and transplantation procedures increased exponentially before 2013. However, the number of UCBTs increased steadily in Asia and China but decreased in the United States and Europe year-on-year from 2013 to 2019. In this review, we focus on the development of UCBT over the past 30 years, the challenges it faces and the strategies for future improvement, including increasing UCB numbers, cord blood unit selection, conditioning regimens and GVHD prophylaxis for UCBT, and management of complications of UCBT.

To determine if miRNA (miR) expression in umbilical cord blood and umbilical cord tissue differs between neonates with early onset sepsis (EOS) versus neonates without true infection.

At present there is no effective treatment of pathologies associated with the death of neurons and glial cells which take place as a result of physical trauma or ischemic lesions of the nervous system. Thus, researchers have high hopes for a treatment based on the use of stem cells (SC), which are potentially able to replace dead cells and synthesize neurotrophic factors and other molecules that stimulate neuroregeneration. We are often faced with ethical issues when selecting a source of SC. In addition to precluding these, human umbilical cord blood (hUCB) presents a number of advantages when compared with other sources of SC. In this review, we consider the key characteristics of hUCB, the results of various studies focused on the treatment of neurodegenerative diseases (Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis), ischemic (stroke) and traumatic injuries of the nervous system and the molecular mechanisms of hUCB-derived mononuclear and stem cells.

The last decade has seen an explosion in the interest in using biologics for regenerative medicine applications, including umbilical cord-derived Wharton's Jelly. There is insufficient literature assessing the amount of growth factors, cytokines, hyaluronic acid, and extracellular vesicles including exosomes in these products. The present study reports the development of a novel Wharton's jelly formulation and evaluates the presence of growth factors, cytokines, hyaluronic acid, and extracellular vesicles including exosomes.

Cancer Stem Cells (CSCs) are a notoriously quiescent subpopulation of cells within heterogeneous tumors exhibiting self-renewal, differentiation and drug-resistant capabilities leading to tumor relapse. Heterogeneous cell populations in tumor microenvironment develop an elaborate network of signalling and factors supporting the CSC population within a niche. Identification of specific biomarkers for CSCs facilitates their isolation. CSCs demonstrate abilities that bypass immune surveillance, exhibit resistance to therapy, and induce cancer recurrence while promoting altered metabolism of the bulk tumor, thereby encouraging metastasis. The fight against cancer is prone to relapse without discussing the issue of CSCs, making it imperative for encapsulation of current studies. In this review, we provide extensive knowledge of recent therapeutics developed that target CSCs via multiple signalling cascades, altered metabolism and the tumor microenvironment. Thorough understanding of the functioning of CSCs, their interaction with different cells in the tumor microenvironment as well as current gaps in knowledge are addressed. We present possible strategies to disrupt the cellular and molecular interplay within the tumor microenvironment and make it less conducive for CSCs, which may aid in their eradication with subsequently better treatment outcomes. In conclusion, we discuss a brief yet functional idea of emerging concepts in CSC biology to develop efficient therapeutics acting on cancer recurrence and metastasis.

Since maternal diabetes may affect fetal development and the umbilical cord provides an extension of the fetal vasculature, we decided to investigate cords' biological responses to maternal diabetic milieu.

Dysregulated transplacental lipid transfer and fetal-placental lipid metabolism affect birthweight, as does maternal hyperglycemia. As the mechanisms are unclear, we aimed to identify the lipids in umbilical cord plasma that were most associated with birthweight. Seventy-five Chinese women with singleton pregnancies recruited into the GUSTO mother-offspring cohort were selected from across the glycemic range based on a mid-gestation 75 g oral glucose tolerance test, excluding pre-existing diabetes. Cord plasma samples collected at term delivery were analyzed using targeted liquid-chromatography tandem mass-spectrometry to determine the concentrations of 404 lipid species across 17 lipid classes. The birthweights were standardized for sex and gestational age by local references, and regression analyses were adjusted for the maternal age, BMI, parity, mode of delivery, insulin treatment, and fasting/2 h glucose, with a false discovery-corrected p < 0.05 considered significant. Ten lysophosphatidylcholines (LPCs) and two lysophosphatidylethanolamines were positively associated with the birthweight percentiles, while twenty-four triacylglycerols were negatively associated with the birthweight percentiles. The topmost associated lipid was LPC 20:2 [21.28 (95%CI 12.70, 29.87) percentile increase in the standardized birthweight with each SD-unit increase in log10-transformed concentration]. Within these same regression models, maternal glycemia did not significantly associate with the birthweight percentiles. Specific fetal circulating lysophospholipids and triacylglycerols associate with birthweight independently of maternal glycemia, but a causal relationship remains to be established.

Transplantation of umbilical cord blood (UCB) is an attractive alternative source of hematopoietic stem cells (HSCs). The unique properties of cord blood and its distinct immune tolerance and engraftment kinetics compared to bone marrow (BM) and peripheral blood progenitor cells, permit a wider disparity in human leukocyte antigen levels between a cord blood donor and recipient after an unrelated umbilical cord blood transplant (UCBT). In addition, it is readily available and has a lowered risk of graft-versus-host disease (GvHD), with similar long-term clinical outcomes, compared to BM transplants. However, the relatively low number of cells administered by UCB units, as well as the associated delayed engraftment and immune reconstitution, pose limitations to the wide application of UCBT. Research into several aspects of UCBT has been evaluated, including the ex vivo expansion of cord blood HSCs and the process of fucosylation to enhance engraftment. Additionally, UCB has also been used in the treatment of several neurodegenerative and cardiovascular disorders with varying degrees of success. In this article, we will discuss the biology, clinical indications, and benefits of UCBT in pediatric and adult populations. We will also discuss future directions for the use of cord blood.

Umbilical cord milking (UCM) improves blood pressure and urine output, and decreases the need for transfusions in comparison to immediate cord clamping (ICC). The immediate effect of UCM in the first few minutes of life and the impact on neonatal resuscitation has not been described.

Mesenchymal stem cells (MSCs) have been identified in multiple types of tissue and exhibit characteristic self-renewal and multi-lineage differentiation abilities. However, the possibility of oncogenic transformation after transplantation is concerning. In this study, we investigated the tumorigenic potential of umbilical cord blood-derived MSCs (hUCB-MSCs) relative to MRC-5 and HeLa cells (negative and positive controls, respectively) both in vitro and in vivo. To evaluate tumorigenicity in vitro, anchorage-independent growth was assessed using the soft agar colony formation assay. hUCB-MSCs and MRC-5 cells formed few colonies, while HeLa cells formed a greater number of larger colonies, indicating that hUCB-MSCs and MRC-5 cells do not have anchorage-independent proliferation potential. To detect tumorigenicity in vivo, hUCB-MSCs were implanted as a single subcutaneous injection into BALB/c-nu mice. No tumor formation was observed in mice transplanted with hUCB-MSCs or MRC-5 cells based on macroand microscopic examinations; however, all mice transplanted with HeLa cells developed tumors that stained positive for a human gene according to immunohistochemical analysis. In conclusion, hUCB-MSCs do not exhibit tumorigenic potential based on in vitro and in vivo assays under our experimental conditions, providing further evidence of their safety for clinical applications.

The development and adoption of cell therapies has been largely limited by difficulties associated with their safety, handling, and storage. Extracellular vesicles (EV) have recently emerged as a likely mediator for the therapeutic effect of cells, offering several advantages over cell therapies. Due to their small size and inability to expand and metastasize, EV are generally considered safer than cell transplantation. Nevertheless, few studies have scrutinized the toxicity profile of EV, particularly after repeated high-dose administration. The present study aimed to evaluate a preparation of small EV obtained from umbilical cord blood mononuclear cells (UCB-MNC-sEV) for its cytotoxicity in different cell lines, as well as its differential accumulation, distribution, and toxicity following repeated intravenous (IV) administrations in a rodent model. In vitro, repeated sEV exposure in concentrations up to 1 × 1011 particles/mL had no deleterious impact on the viability or metabolic activity of peripheral blood mononuclear cells, THP-1 monocytes, THP-1-derived macrophages, normal dermal human fibroblasts, or human umbilical vein endothelial cells. DiR-labelled sEV, injected intravenously for four weeks in healthy rats, were detected in clearance organs, particularly the kidneys, spleen, and liver, similarly to control dye. Moreover, repeated administrations for six and twelve weeks of up to 1 × 1010 total particles of sEV dye were well-tolerated, with no changes in general haematological cell counts, or kidney and liver toxicity markers. More importantly, unlabelled sEV likewise did not induce significant alterations in cellular and biochemical blood parameters, nor any morphological changes in the heart, kidney, lung, spleen, or liver tissue. In sum, our data show that UCB-MNC-sEV have no significant toxicity in vitro or in vivo, even when administered repeatedly at high concentrations, therefore confirming their safety profile and potential suitability for future clinical use.

Umbilical cord blood transplant (UCBT) is used for patients who do not have a matched donor, but engraftment often takes longer than with a standard allogeneic transplant, likely increasing the risk for infection. We characterized specific infections and outcomes in adults undergoing UCBT at our 2 centers.

We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) to evaluate the efficacy of chlorhexidine application to the umbilical cord in neonates. We searched MEDLINE and other electronic databases, and included all RCTs that evaluated the effect of single or multiple chlorhexidine cord applications on the neonatal mortality rate (NMR) and/or the incidence of systemic sepsis and omphalitis. A total of six RCTs-four community-based cluster RCTs and two hospital-based trials-were included in the review. Of the four cluster RCTs, three were conducted in South Asia in settings with high rates of home births (>92%) while the fourth, available only as an abstract, was conducted in Africa. Pooled analysis by the 'intention-to-treat' principle showed a significant reduction in NMR after chlorhexidine application (four studies; relative risk (RR) 0.85; 95% confidence interval (CI) 0.76 to 0.95; fixed effects (FE) model). On subgroup analysis, only multiple applications showed a significant effect (four studies; RR 0.88; 95% CI 0.78 to 0.99) whereas a single application did not (one study; RR 0.86; 0.73 to 1.02). Similarly, only the community-based trials showed a significant reduction in NMR (three studies; RR 0.86; 95% CI 0.77 to 0.95), while the hospital-based study did not find any effect (RR 0.11; 0.01 to 2.03). Since all the studies were conducted in high-NMR settings (⩾30 per 1000 live births), we could not determine the effect in settings with low NMRs. Only one study-a hospital-based trial from India-reported the incidence of neonatal sepsis; it did not find a significant reduction in any sepsis (RR 0.67; 95% CI 0.35 to 1.28). Pooled analysis of community-based studies revealed significant reduction in the risk of omphalitis in infants who received the intervention (four studies; RR 0.71; 95% CI 0.62 to 0.81). The hospital-based trial had no instances of omphalitis in either of the two groups. Chlorhexidine application delayed the time to cord separation (four studies; mean difference 2.11 days; 95% CI 2.07 to 2.15; FE model). Chlorhexidine application to the cord reduces the risk of neonatal mortality and omphalitis in infants born at home in high-NMR settings. Routine chlorhexidine application, preferably daily for 7 to 10 days after birth, should therefore be recommended in these infants. Given the paucity of evidence, there is presently no justification for recommending this intervention in infants born in health facilities and/or low-NMR settings.

Ovarian injury because of chemotherapy can decrease the levels of sexual hormones and potentia generandi of patients, thereby greatly reducing quality of life. The goal of this study was to investigate which transplantation method for human umbilical cord mesenchymal stem cells (HUMSCs) can recover ovarian function that has been damaged by chemotherapy. A rat model of ovarian injury was established using an intraperitoneal injection of cyclophosphamide. Membrane-labelled HUMSCs were subsequently injected directly into ovary tissue or tail vein. The distribution of fluorescently labelled HUMSCs, estrous cycle, sexual hormone levels, and potentia generandi of treated and control rats were then examined. HUMSCs injected into the ovary only distributed to the ovary and uterus, while HUMSCs injected via tail vein were detected in the ovary, uterus, kidney, liver and lung. The estrous cycle, levels of sex hormones and potentia generandi of the treated rats were also recovered to a certain degree. Moreover, in some transplanted rats, fertility was restored and their offspring developed normally. While ovary injection could recover ovarian function faster, both methods produced similar results in the later stages of observation. Therefore, our results suggest that transplantation of HUMSCs by tail vein injection represents a minimally invasive and effective treatment method for ovarian injury.