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With the potential for self-renewal and differentiation, the possibilities for stem cells are enormous. One specific type of stem cell, the hematopoietic progenitor cell (HPC), which is derived from umbilical cord blood (as well as adult bone marrow and mobilized peripheral blood), holds particular promise. To make the most of these HPCs, the Institute of Medicine was asked to consider the optimal structure for a national cord blood program and to address pertinent issues related to maximizing the potential of stem cell technology. Cord Blood: Establishing a National Hematopoietic Stem Cell Bank Program examines: The role of cord blood in stem cell transplantation The current status of blood banks already in existence The optimal structure for the cord blood program The current use and utility of cord blood for stem cell transplants The best way to advance the use of cord blood units and make them available for research Expert advice from leaders in the fields of economics, public health, medicine, and biostatistics combine to make this very timely and topical book useful to a number of stakeholders.

Cord blood (CB) cells that express CD34 have extensive hematopoietic capacity and rapidly divide ex vivo in the presence of cytokine combinations; however, many of these CB CD34+ cells lose their marrow-repopulating potential. To overcome this decline in function, we treated dividing CB CD34+ cells ex vivo with several histone deacetylase inhibitors (HDACIs). Treatment of CB CD34+ cells with the most active HDACI, valproic acid (VPA), following an initial 16-hour cytokine priming, increased the number of multipotent cells (CD34+CD90+) generated; however, the degree of expansion was substantially greater in the presence of both VPA and cytokines for a full 7 days. Treated CD34+ cells were characterized based on the upregulation of pluripotency genes, increased aldehyde dehydrogenase activity, and enhanced expression of CD90, c-Kit (CD117), integrin α6 (CD49f), and CXCR4 (CD184). Furthermore, siRNA-mediated inhibition of pluripotency gene expression reduced the generation of CD34+CD90+ cells by 89%. Compared with CB CD34+ cells, VPA-treated CD34+ cells produced a greater number of SCID-repopulating cells and established multilineage hematopoiesis in primary and secondary immune-deficient recipient mice. These data indicate that dividing CB CD34+ cells can be epigenetically reprogrammed by treatment with VPA so as to generate greater numbers of functional CB stem cells for use as transplantation grafts.

The use of marrow stem cells to treat seven children with severe epidermolysis bullosa caused by loss-of-function mutations in COL7A, the gene encoding type VII collagen (C7), was examined. The investigators observed increases in C7 deposition, the presence of donor cells in the skin, and an amelioration of symptoms. Loss of skin integrity that leads to trauma-induced blisters and erosions is a defining feature of epidermolysis bullosa, a heterogeneous group of more than 20 inherited blistering diseases with highly variable clinical severity. 1 One of the most severe forms is recessive dystrophic epidermolysis bullosa, caused by loss-of-function mutations in the collagen type VII (C7) gene ( COL7A1 ). 2 – 6 These mutations result in severely diminished expression of C7, a collagen localized at the dermal–epidermal junction. C7 is the major component of the anchoring fibrils that tether the epidermal basement membrane to the dermal matrix. In the absence of normal C7 . . .

Outcomes were compared in adults with leukemia who had received hematopoietic stem-cell transplants from unrelated donors. Patients received HLA-matched bone marrow, bone marrow with one HLA mismatch, or cord blood with one or two mismatches. The outcomes were most favorable in recipients of HLA-matched marrow but similar in those who had received mismatched marrow or cord blood. Patients received HLA-matched bone marrow, bone marrow with one HLA mismatch, or cord blood with one or two mismatches. The results of this study reinforce the clinical advantages of cord blood as a source of hematopoietic stem cells. Treatment of leukemia with transplantation of allogeneic bone marrow or stem cells from the peripheral blood is limited by the scarcity of HLA-matched related donors. Only 30 percent of otherwise eligible patients with leukemia in the United States have a related histocompatible donor and, of the remainder, only about 20 percent receive a transplant from an unrelated donor or an HLA-mismatched related donor. 1 The higher risk of acute and chronic graft-versus-host disease (GVHD) is an important drawback to be considered when grafts from unrelated donors or related donors with partially matched HLA antigens are used. 2 – 5 Cord-blood grafts from unrelated . . .

This report compares major outcomes after treatment of acute leukemia in adults with either bone marrow or umbilical-cord blood from an unrelated donor. Except for delayed recovery of neutrophils and a reduced risk of graft-versus-host disease in recipients of cord blood, the results with cord blood and bone marrow were similar. It has become apparent that transplanting cord blood into adults is feasible. This report shows that cord blood is an alternative source of hematopoietic stem cells for transplantation. Umbilical-cord blood is considered an alternative to bone marrow as a source of hematopoietic stem cells for transplantation, 1 and its use in adults with hematologic cancers is increasing. 2 There is considerable evidence that cord blood is a promising option for patients who lack an HLA-matched bone marrow donor. 3 – 9 The advantages of cord blood are the immediate availability of cells, the absence of risk to the donor, and a lower need for HLA compatibility between the donor and the recipient. 8 – 11 A limiting factor is the low number of hematopoietic stem cells in a unit of cord blood. For this . . .

Abstract 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 blood stem cells are an alternative source of hematopoietic stem cells that allows greater disparity between HLA levels between donors and recipients. - Cord blood stem cell transplantation has comparable clinical outcomes and a lower risk of graft-versus-host disease than other sources of stem cells. - Limitations in terms of the low number of cells administered by units and slow engraftment, are areas in which additional research is being conducted. - Besides their application in oncology, they are also used in the treatment of several neurodegenerative and cardiovascular disorders

Stroke is a major cause of death and long‐term disability, affecting one in six people worldwide. The only currently available approved pharmacological treatment for ischemic stroke is tissue plasminogen activator; however, relatively few patients are eligible for this therapy. We hypothesized that intravenous (IV) infusion of banked unrelated allogeneic umbilical cord blood (UCB) would improve functional outcomes in patients with ischemic stroke. To investigate this, we conducted a phase I open‐label trial to assess the safety and feasibility of a single IV infusion of non‐human leukocyte antigen (HLA) matched, ABO matched, unrelated allogeneic UCB into adult stroke patients. Ten participants with acute middle cerebral artery ischemic stroke were enrolled. UCB units were matched for blood group antigens and race but not HLA, and infused 3–9 days post‐stroke. The adverse event (AE) profile over a 12 month postinfusion period indicated that the treatment was well‐tolerated in these stroke patients, with no serious AEs directly related to the study product. Study participants were also assessed using neurological and functional evaluations, including the modified Rankin Score (mRS) and National Institute of Health Stroke Scale (NIHSS). At 3 months post‐treatment, all participants had improved by at least one grade in mRS (mean 2.8 ± 0.9) and by at least 4 points in NIHSS (mean 5.9 ± 1.4), relative to baseline. Together, these data suggest that a single i.v. dose of allogeneic non‐HLA matched human UCB cells is safe in adults with ischemic stroke, and support the conduct of a randomized, placebo‐controlled phase 2 study. Stem Cells Translational Medicine 2018;7:521–529 We conducted a phase I open‐label trial to assess the safety and feasibility of a single IV infusion of non‐human leukocyte antigen matched, ABO matched, unrelated allogeneic umbilical cord blood (UCB) into adult patients who had recently experienced an acute ischemic stroke. UCB was administered between 3 and 10 days post‐stroke.

Background Thiotepa-busulfan-fludarabine (TBF) is a widely used conditioning regimen in single umbilical cord blood transplantation (SUCBT). More recently, it was introduced in the setting of non-T cell depleted haploidentical stem cell transplantation (NTD-Haplo). Whether TBF based conditioning provides additional benefit in transplantation from a particular alternative donor type remains to be established. Methods This was a retrospective study based on an international European registry. We compared outcomes of de-novo acute myeloid leukemia patients in complete remission receiving NTD-Haplo ( n  = 186) vs. SUCBT ( n  = 147) following myeloablative conditioning (MAC) with TBF. Median follow-up was 23 months. Treatment groups resembled in baseline characteristics. Results SUCBT was associated with delayed engraftment and higher graft failure. In multivariate analysis no statistically significant differences were observed between the two groups in terms of acute or chronic graft-versus-host disease (GvHD) (HR = 1.03, p  = 0.92 or HR = 1.86, p  = 0.21) and relapse incidence (HR = 0.8, p  = 0.65). Non-relapse mortality (NRM) was significantly higher in SUCBT as compared to NTD-Haplo (HR = 2.63, p  = 0.001); moreover, SUCBT did worse in terms of overall survival (HR = 2.18, p  = 0.002), leukemia-free survival (HR = 1.94, p  = 0.007), and GvHD relapse-free survival (HR = 2.38, p  = 0.0002). Conclusions Our results suggest that TBF-MAC might allow for a potent graft-versus-leukemia, regardless of the alternative donor type. Furthermore, in patients receiving TBF-MAC, survival with NTD-Haplo may be better compared to SUCBT due to decreased NRM.

Cerebral palsy (CP) is a condition affecting young children that causes lifelong disabilities. Umbilical cord blood cells improve motor function in experimental systems via paracrine signaling. After demonstrating safety, we conducted a phase II trial of autologous cord blood (ACB) infusion in children with CP to test whether ACB could improve function (ClinicalTrials.gov, NCT01147653; IND 14360). In this double‐blind, placebo‐controlled, crossover study of a single intravenous infusion of 1–5 × 107 total nucleated cells per kilogram of ACB, children ages 1 to 6 years with CP were randomly assigned to receive ACB or placebo at baseline, followed by the alternate infusion 1 year later. Motor function and magnetic resonance imaging brain connectivity studies were performed at baseline, 1, and 2 years post‐treatment. The primary endpoint was change in motor function 1 year after baseline infusion. Additional analyses were performed at 2 years. Sixty‐three children (median age 2.1 years) were randomized to treatment (n = 32) or placebo (n = 31) at baseline. Although there was no difference in mean change in Gross Motor Function Measure‐66 (GMFM‐66) scores at 1 year between placebo and treated groups, a dosing effect was identified. In an analysis 1 year post‐ACB treatment, those who received doses ≥2 × 107/kg demonstrated significantly greater increases in GMFM‐66 scores above those predicted by age and severity, as well as in Peabody Developmental Motor Scales‐2 Gross Motor Quotient scores and normalized brain connectivity. Results of this study suggest that appropriately dosed ACB infusion improves brain connectivity and gross motor function in young children with CP. Stem Cells Translational Medicine 2017;6:2071–2078 Change in brain connectivity 1 year after autologous cord blood treatment by cell dose. The nodes and edges included are those that demonstrated significantly increased improvement in children receiving high doses compared with those receiving low doses, as indicated by the color chart, with insignificant nodes shown in gray. High dose ≥2 × 107/kg, low dose <2 × 107/kg.

The current standard first-line therapy for aplastic anemia (AA) consists of antithymocyte globulin (ATG), cyclosporine, and thrombopoietin receptor agonists (TPO-RAs). A subset of patients exhibit treatment intolerance or develop refractory/relapsed disease, for whom treatment options are limited. Umbilical cord blood exhibits immunomodulatory effects, regulates the bone marrow microenvironment, and promotes hematopoietic reconstitution, thereby demonstrating therapeutic potential for AA. In this prospective clinical study, cord blood infusion was administered in combination with cyclosporine and hetrombopag for the treatment of AA (n = 11). The primary endpoint was the hematologic response at 3 months post-treatment. By 3 months, 8 of 11 patients achieved at least one lineage hematologic response. By 6 months, 3 patients attained complete response (CR), 5 achieved partial response (PR), yielding an overall response rate (ORR) of 8/11. After a median follow-up of 23 months, 5 patients maintained sustained CR and 3 sustained PR, with the ORR remaining at 8/11. The median time to trilineage response was 112 days (range: 18–168 days) among 8 responsive patients. Two patients with SAA refractory to treatment succumbed to pulmonary infections and pneumorrhagia. No significant adverse reactions were observed in cord blood-treated patients. This small-scale study introduces a novel regimen combining umbilical cord blood infusion, cyclosporine, and hetrombopag for treating aplastic anemia. With a median follow-up of 23 months, the overall response rate reached 8/11 and the CR rate 5/11. The safety and efficacy of this regimen were preliminarily assessed, suggesting a potential therapeutic alternative for patients ineligible for standard immunosuppressive therapy.