Current Status and Future Prospects of Perinatal Stem Cells.

The placenta is a temporary organ that is discarded after birth and is one of the most promising sources of various cells and tissues for use in regenerative medicine and tissue engineering, both in experimental and clinical settings. The placenta has unique, intrinsic features because it plays many roles during gestation: it is formed by cells from two individuals (mother and fetus), contributes to the development and growth of an allogeneic fetus, and has two independent and interacting circulatory systems. Different stem and progenitor cell types can be isolated from the different perinatal tissues making them particularly interesting candidates for use in cell therapy and regenerative medicine. The primary source of perinatal stem cells is cord blood. Cord blood has been a well-known source of hematopoietic stem/progenitor cells since 1974. Biobanked cord blood has been used to treat different hematological and immunological disorders for over 30 years. Other perinatal tissues that are routinely discarded as medical waste contain non-hematopoietic cells with potential therapeutic value. Indeed, in advanced perinatal cell therapy trials, mesenchymal stromal cells are the most commonly used. Here, we review one by one the different perinatal tissues and the different perinatal stem cells isolated with their phenotypical characteristics and the preclinical uses of these cells in numerous pathologies. An overview of clinical applications of perinatal derived cells is also described with special emphasis on the clinical trials being carried out to treat COVID19 pneumonia. Furthermore, we describe the use of new technologies in the field of perinatal stem cells and the future directions and challenges of this fascinating and rapidly progressing field of perinatal cells and regenerative medicine.

Cord blood transplantation for acute leukemia.

INTRODUCTION: Umbilical cord blood transplantation (UCBT) is a suitable alternative for patients with acute leukemia (AL) in need of an allograft and who lack an HLA-matched donor. Single-institution and registry studies have shown that, in both children and adults with AL, the outcome of UCBT is comparable to that of matched unrelated donor. At the same time, these studies have highlighted some limitations of UCBT, such as increased early mortality and delayed recovery of both hematopoietic and immune compartment, which hamper a more widespread adoption of this approach. AREAS COVERED: In this review, we will analyze the current results of UCBT in children and adults with AL, including comparisons with other hematopoietic stem cell sources and transplant strategies. We will also discuss important factors to be considered when selecting UCB units, as well as future strategies to further improve the outcome of UCBT recipients. EXPERT OPINION: The utilization of UCBT for the treatment of AL patients has decreased in recent years. However, recent clinical data suggesting that UCBT might offer better results in patients with minimal residual disease, as well as innovative strategies to facilitate engraftment, reduce transplant-related mortality, and optimize anti-leukemic activity, may pave the way toward a second youth for use of UCB cells.

Transplantation of IFN-γ Primed hUCMSCs Significantly Improved Outcomes of Experimental Autoimmune Encephalomyelitis in a Mouse Model.

The aim of this study was to investigate potential therapeutic effects of IFN-γ primed human umbilical cord mesenchymal stem cell (IFN-γ-hUCMSCs) transplantation on experimental autoimmune encephalomyelitis (EAE) in mice. In this study, EAE mouse model was established by MOG35-55 immunization method. Outcomes of the EAE mice in terms of body weight and clinical symptoms were analyzed. Electromyography (EMG) was performed to evaluate nerve conduction. ELISA was applied to quantify inflammatory cytokine levels in serum. Our results showed that IFN-γ could up-regulate protein expression of indoleamine 2, 3-dioxygenease 1 (IDO1), an important molecule released by MSCs to exert their immune suppressive activity (p < 0.01). In this study treatment efficacy for EAE was compared between transplantation of hUCMSCs alone and the IFN-γ-hUCMSCs which were cultured in the presence of IFN-γ for 48 h prior to be harvested for transplantation. Compared with hUCMSCs alone and control (PBS transfusion) group, transplantation of the IFN-γ-hUCMSCs could significantly alleviate the body weight loss and clinical symptoms of EAE mice (p < 0.05). Consistently EMG latency was significantly improved in treatment groups (p < 0.001), and the IFN-γ-hUCMSCs group was even better than the hUCMSCs group (p < 0.05). Moreover, the concentrations of IL-17A and TNF-α in serum of the mice treated by IFN-γ-hUCMSCs were significantly lower than hUCMSCs alone and controls, respectively (p < 0.05). In few of the roles of IL-17A and TNF-α in the pathogenesis of EAE, IFN-γ-hUCMSCs treatment associated-suppression of IL-17A and TNF-α expression may contribute in part to their therapeutic effects on EAE. In sum, our study highlights a great clinical potential of IFN-γ-hUCMSCs for multiple sclerosis (MS) treatment.

Cord Blood Banking and Transplantation in a National Program: Thirteen Years of Experience.

BACKGROUND: The umbilical cord blood bank at the Mexican Institute of Social Security (IMSS-CBB) was established in January 2005. This lead to the development of the UCB transplantation program. Herein, we describe the experience generated during these 13 years. STUDY DESIGN AND METHODS: Donor selection, as well as UCB collection, processing, and banking were performed under good manufacturing practices and standard operating procedures. UCB units were thawed, processed, and released for transplantation based on HLA and nucleated cell content. RESULTS: From January 2005-December 2017, 1,298 UCB units were banked; 164 of them were released for transplantation, and 118 UCB transplants were performed. Ninety-four transplants were performed in pediatric patients and 24 in adults. Sixty percent of them corresponded to patients with leukemia, 19% were patients with marrow failure, and the rest had immunodeficiency, hemoglobinopathy, metabolic disorders, or solid tumors. Engraftment was observed in 67 patients (57% of transplanted patients) and 64% of them were still alive when writing this article. In contrast, only 13 of the 51 (25%) non-engrafting patients were alive. At the time of writing this article, the disease-free survival rate was 37%, and the overall survival rate was 47%, with survival periods of 161-3,721 days. CONCLUSION: The IMSS UCB banking and transplantation program has had a significant impact for many IMSS patients. The hematopoietic transplantation program at our institution has benefited from the use of UCB as a source of transplantable cells.

Portrayal of umbilical cord blood research in the North American popular press: promise or hype?

Aim: This study examined how umbilical cord blood (UCB) use was portrayed in the English language North American popular press. Methods: Directed content analysis was conducted on 400 articles from 2007 to 2017 containing 'cord blood,' published by the most read Canadian and American news sources. Results: A total of 86.3% of the articles detailed UCB treatments and therapies, the majority of which align with clinical evidence. Some articles portrayed speculative/experimental therapies as efficacious. Public and private banking initiatives received substantial attention, and were portrayed diversely. Promotional narrative messaging was evident around private banking. Conclusion: Findings demonstrate the need for continual monitoring of the media portrayals of UCB as stem cell and transplantation research develops and as clinics continue to operate.

Improvement of early mortality in single-unit cord blood transplantation for Japanese adults from 1998 to 2017.

The major limitation of cord blood transplantation (CBT) for adults remains the delayed hematopoietic recovery and higher incidence of graft failure, which result in a higher risk of early mortality in CBT. We evaluated early overall survival (OS), non-relapse mortality (NRM), neutrophil engraftment, acute graft-vs-host disease, and cause of early death among 9678 adult patients who received single-unit CBT in Japan between 1998 and 2017. The probability of OS at 100 days was 64.4%, 71.7%, and 78.9% for the periods 1998 to 2007, 2008 to 2012, and 2013 to 2017, respectively (P < .001). The cumulative incidences of NRM at 100 days during the same period were 28.3%, 20.8%, and 14.6%, respectively (P < .001). The cumulative incidences of neutrophil engraftment were also improved during the same period (P < .001). The most common cause of death within 100 days after CBT was bacterial infection in 1998 to 2007 and primary disease in the latter two time periods. Across the three time periods, the proportions of deaths from bacterial and fungal infection, graft failure, hemorrhage, sinusoidal obstructive syndrome, and organ failure decreased in a stepwise fashion. Landmark analysis of OS and NRM after 100 days showed that OS did not change over time in the multivariate analysis. Our registry-based data demonstrated a significant improvement of early OS after CBT for adults over the past 20 years. The landmark analysis suggested that improvement of early mortality could lead to an improvement of long-term OS after CBT.

Single cord blood transplantation in Japan; expanding the possibilities of CBT.

Cord blood (CB) has been an alternative stem cell source for patients with a wide variety of hematological diseases. Cord blood confers the advantages of rapid availability and higher tolerance to two HLA antigen mismatches compared with unrelated donors, and this has increased opportunities for patients who do not have suitable donors or require urgent transplantation. Although the higher rate of engraftment failure remains a serious concern after cord blood transplantation (CBT), the mechanisms underlying this risk have gradually been clarified, which has helped to improve engraftment. Recent studies of CBT and other alternatives have reported comparable outcomes. Moreover, CBT shows promise even when patients are in a non-remission status, which may reflect the potent graft-versus-leukemia effect of CB. Here we compare the most recent outcomes of CBT with those of other stem cell sources and discuss the potential of CB and several outstanding issues that require resolution.

Alternative Donor/Unrelated Donor Transplants for the ß-Thalassemia and Sickle Cell Disease.

Considerable progress with respect to donor source has been achieved in allogeneic stem cell transplant for patients with hemoglobin disorders, with matched sibling donors in the 1980s, matched unrelated donors and cord blood sources in the 1990s, and haploidentical donors in the 2000s. Many studies have solidified hematopoietic progenitors from matched sibling marrow, cord blood, or mobilized peripheral blood as the best source-with the lowest graft rejection and graft versus host disease (GvHD), and highest disease-free survival rates. For patients without HLA-matched sibling donors, but who are otherwise eligible for transplant, fully allelic matched unrelated donor (8/8 HLA-A, B, C, DRB1) appears to be the next best option, though an ongoing study in patients with sickle cell disease will provide data that are currently lacking. There are high GvHD rates and low engraftment rates in some of the unrelated cord transplant studies. Haploidentical donors have emerged in the last decade to have less GvHD; however, improvements are needed to increase the engraftment rate. Thus the decision to use unrelated cord blood units or haploidentical donors may depend on the institutional expertise; there is no clear preferred choice over the other. Active research is ongoing in expanding cord blood progenitor cells to overcome the limitation of cell dose, including the options of small molecule inhibitor compounds added to ex vivo culture or co-culture with supportive cell lines. There are inconsistent data from using 7/8 or lower matched unrelated donors. Before routine use of these less matched donor sources, work is needed to improve patient selection, conditioning regimen, GvHD prophylaxis, and/or other strategies.

Cord Blood Banking for Potential Future Transplantation.

This policy statement is intended to provide information to guide pediatricians, obstetricians, and other medical specialists and health care providers in responding to parents' questions about cord blood donation and banking as well as the types (public versus private) and quality of cord blood banks. Cord blood is an excellent source of stem cells for hematopoietic stem cell transplantation in children with some fatal diseases. Cord blood transplantation offers another method of definitive therapy for infants, children, and adults with certain hematologic malignancies, hemoglobinopathies, severe forms of T-lymphocyte and other immunodeficiencies, and metabolic diseases. The development of universal screening for severe immunodeficiency assay in a growing number of states is likely to increase the number of cord blood transplants. Both public and private cord blood banks worldwide hold hundreds of thousands of cord blood units designated for the treatment of fatal or debilitating illnesses. The procurement, characterization, and cryopreservation of cord blood is free for families who choose public banking. However, the family cost for private banking is significant and not covered by insurance, and the unit may never be used. Quality-assessment reviews by several national and international accrediting bodies show private cord blood banks to be underused for treatment, less regulated for quality control, and more expensive for the family than public cord blood banks. There is an unquestionable need to study the use of cord blood banking to make new and important alternative means of reconstituting the hematopoietic blood system in patients with malignancies and blood disorders and possibly regenerating tissue systems in the future. Recommendations regarding appropriate ethical and operational standards (including informed consent policies, financial disclosures, and conflict-of-interest policies) are provided for physicians, institutions, and organizations that operate or have a relationship with cord blood banking programs. The information on all aspects of cord blood banking gathered in this policy statement will facilitate parental choice for public or private cord blood banking.

The role of policies and networks in development of cord blood usage in China.

Research regarding the use of cord blood (CB) has focused on antigen match and the number of stem cells, with policies and networks related to its use being under researched. This article is based on fieldwork in China from 2013 to 2015 and examines ways that the studied CB bank enhances CB usage in China. This article identifies that in addition to finding a match, CB use is linked to the policies and networks, release fee and public awareness that enable CB usage development.

Umbilical Cord Blood Transplantation: Challenges and Future Directions.

Since the first successful allogeneic transplants performed in Seattle 50 years ago, the field of transplantation has evolved considerably, with improvements in human leukocyte antigen typing, patient selection, reduced intensity regimens, and graft-versus-host disease prophylaxis. A major breakthrough has been the availability of more donor options, first via the National Marrow Donor Program-Be the Match [Biol Blood Marrow Transplant 2008;14:2-7]. Then, in the 1990s, unrelated umbilical cord blood transplantation became available, first for children and then for adults [New Engl J Med 1996;35:157-166]. More recently mismatched unrelated transplants and haploidentical donor options became available [Blood 2011;118:282-288]. In 2017, there is a donor for almost every patient who needs a transplant. In this review, we will discuss the state of the science (and art) of cord blood transplant, focusing on successes, challenges, and future directions. Stem Cells Translational Medicine 2017;6:1312-1315.

A Single-center, Retrospective Study of Cryopreserved Umbilical Cord for Wound Healing in Patients Suffering From Chronic Wounds of the Foot and Ankle.

OBJECTIVE: Chronic wounds are a significant issue not only in wound care facilities, but also in daily practice for general practitioners and specialists across a wide variety of disciplines. These wounds are primarily foot or lower extremity ulcers and can result from a combination of factors including neuropathy, vascular insufficiency, and impaired wound healing. In addition to a significant health care cost, ulcerations have a devastating impact on virtually every aspect of the affected patient's daily life such as extensive pain, sleep impairment, restricted mobility, and work capacity. The objective of this single-center, retrospective study was to evaluate the clinical effectiveness of a human cryopreserved umbilical cord (cUC) allograft as an advanced therapeutic treatment modality for chronic, nonhealing lower extremity wounds. MATERIALS AND METHODS: Following Institutional Review Board approval, data from all qualifying patients who had received cUC tissue treatment during a period of 16 months was collected retrospectively. A total of 57 patients presenting with 64 chronic wounds who received treatment with cUC and were treated by the same surgeon at a single wound care center were analyzed. RESULTS: The average initial wound area was 6.85 cm2 ± 16.29 cm2. Overall, 51 of 64 wounds achieved complete healing, resulting in an overall wound-healing rate of 79.7%. For wounds that healed, the average wound-healing time was 5.53 ± 3.93 weeks, and an average of 3.43 ± 2.42 applications of cUC were used to achieve healing. CONCLUSION: Overall, these results demonstrate cUC may be effective in promoting the healing of chronic, lower extremity ulcers. In addition, this study suggests cUC may be a useful advanced tissue treatment modality with the potential not only to improve patient quality of life, but also positively impact rising health care costs associated with long-term treatment of such ulcers. Further exploration, including prospective, randomized controlled trials, is warranted to better understand the effectiveness of cUC.

Differentiation of Donor-Derived Cells Into Microglia After Umbilical Cord Blood Stem Cell Transplantation.

Recent studies have indicated that microglia originate from immature progenitors in the yolk sac. After birth, microglial populations are maintained under normal conditions via self-renewal without the need to recruit monocyte-derived microglial precursors. Peripheral cell invasion of the brain parenchyma can only occur with disruption of the blood-brain barrier. Here, we report an autopsy case of an umbilical cord blood transplant recipient in whom cells derived from the donor blood differentiated into ramified microglia in the recipient brain parenchyma. Although the blood-brain barrier and glia limitans seemed to prevent invasion of these donor-derived cells, most of the invading donor-derived ramified cells were maintained in the cerebral cortex. This result suggests that invasion of donor-derived cells occurs through the pial membrane.

Cord Blood Banking in the Arab World: Current Status and Future Developments.

Umbilical cord blood transplants are now used to treat numerous types of immune- and blood-related disorders and genetic diseases. Cord blood (CB) banks play an important role in these transplants by processing and storing CB units. In addition to their therapeutic potential, these banks raise ethical and regulatory questions, especially in emerging markets in the Arab world. In this article, the authors review CB banking in five countries in the region, Jordan, Saudi Arabia, Egypt, Qatar, and the United Arab Emirates, selected for their different CB banking policies and initiatives. In assessing these case studies, the authors present regional trends and issues, including religious perspectives, policies, and demographic risk factors. This research suggests strong incentives for increasing the number of CB units that are collected from and available to Arab populations. In addition, the deficit in knowledge concerning public opinion and awareness in the region should be addressed to ensure educated decision-making.

Advances in unrelated and alternative donor hematopoietic cell transplantation for nonmalignant disorders.

PURPOSE OF REVIEW: The role of hematopoietic cell transplantation in non-malignant disorders has increased exponentially with the recognition that multiple diseases can be controlled or cured if engrafted with donor-derived cells. This review provides an overview of advances made in alternative donor transplants for nonmalignant disorders. RECENT FINDINGS: Stem cell sources, novel transplant methods, and sophisticated supportive care have simultaneously made giant strides toward improving the safety and efficacy of hematopoietic cell transplantation. This has led to the utilization of marrow, cord, peripheral blood stem cell and haploidentical stem cell sources, and novel reduced toxicity or reduced intensity conditioning regimens to transplant non-malignant disorders such as immune dysfunctions, marrow failure syndromes, metabolic disorders and hemoglobinopathies. Transplant complications such as graft rejection, infections, and graft versus host disease are better combated in this modern era of medicine, achieving better survival with decreased late effects. These aspects of transplant for non-malignant disorders are discussed. SUMMARY: This review presents the progress made in the realm of hematopoietic cell transplantation for non-malignant disorders. It advocates the consideration of alternative donor transplants in the absence of human leukocyte antigen matched siblings when indicated by disease severity. The ultimate goal is to provide curative transplant options for more patients that can benefit from this intervention, prior to detrimental outcomes.

Advances in umbilical cord blood transplant: an overview of the 12th International Cord Blood Symposium, San Francisco, 5-7 June 2014.

From 5 to 7 June the 12th Annual International Cord Blood Symposium was held in San Francisco. The meeting was devoted to advances in umbilical cord blood research with a major focus on translational and clinical results in cord blood transplant and in regenerative medicine. Over 3 days, a comprehensive summary of the state of the art was provided. We have summarized the most important data, organized around the following themes: use of umbilical cord blood for tissue repair, new indications for umbilical cord blood unit stem cell transplant (CBU SCT), enhancing count recovery after CBU SCT, improving outcomes, product quality and financial and cost considerations.

Concise review: umbilical cord blood transplantation: past, present, and future.

Allogeneic hematopoietic stem cell transplantation is an important treatment option for fit patients with poor-risk hematological malignancies; nevertheless, the lack of available fully matched donors limits the extent of its use. Umbilical cord blood has emerged as an effective alternate source of hematopoietic stem cell support. Transplantation with cord blood allows for faster availability of frozen sample and avoids invasive procedures for donors. In addition, this procedure has demonstrated reduced relapse rates and similar overall survival when compared with unrelated allogeneic hematopoietic stem cell transplantation. The limited dose of CD34-positive stem cells available with single-unit cord transplantation has been addressed by the development of double-unit cord transplantation. In combination with improved conditioning regimens, double-unit cord transplantation has allowed for the treatment of larger children, as well as adult patients with hematological malignancies. Current excitement in the field revolves around the development of safer techniques to improve homing, engraftment, and immune reconstitution after cord blood transplantation. Here the authors review the past, present, and future of cord transplantation.