As far as the clinical use we need to realize how UCB is rapidly becoming the standard care or an important alternative for many onco-hematological disorders nowadays and how UCB can gain credit for many other diseases.
Onco-hematological disorders
The comparison between UCB and BM showed that outcomes are similar, suggesting an important role for UCB as a source of stem cells in these patients [59]. Clinical trials relative to UCB for onco-hematology malignancies in children report that a cell dose of 2.0×107/kg at cryopreservation is frequently found out and that engraftment is consistently above 90% despite the number of nucleated or CD34+ cells being about 1 log lower than in adult donor grafts [60]. The incidence of GvHD after UCB transplant is very low in comparison to that of adult HSC grafts, despite the fact that most UCB grafts are HLA-mismatched [55]. The low incidence of GvHD has been reported in literature as naiveté of the neonatal immune system [51]. By the way, the reduced alloreactivity does not compromise long-term risks of relapse. In clinical trials comparing UCB with adult HSC grafts in the pediatric setting, relapse rates after UCB transplantation range from 15% to 40% and survival from 40% to 60% [61]. In many centers, UCB has become the preferred source of unrelated HSCs for transplantation. It is expected that the indications of UCB for the treatment of children with malignancies will continue to grow. Large multicenter studies, such as the Bone Marrow Transplantation-Clinical Trials Network is testing a randomized comparison of one or two UCB units for children with leukemia, are likely to contribute to this growth [61]. Recently, Verneris MR et al. [62] have reported the risk factors associated with leukemia relapse following myeloablative CB-SCs transplant in recipients of 2 units CB-SCs: patients with acute leukemia (n=177; 88 affected by lymphoblastic leukemia and 89 with acute myeloid leukemia) have been submitted to treatment. Recipients received a CB-SCs graft composed of either 1 (47%) or 2 (53%) partially HLA-matched human leukocyte antigen unit. Relapse rate was higher in advanced disease recipients with a trend toward less relapse in recipients of 2 UCB units, with progression free survival of 40% and 51% for single- and double-unit recipients respectively [62]. Clinical trials relative to UCB for onco-hematology malignancies in adult report that the main limiting factor is the available cell doses from a single UCB unit [61].
Endocrine disorders and diabetes
Each year about 15000 US youths are diagnosed with T1D and 1.5 million individuals have T1D overall in the USA [54]. T1D resulted from autoimmune destruction of β-cells in the pancreatic islets responsible for insulin production. Diabetic complications include cardiomyopathy, coronary artery disease, peripheral vascular disease and neurological complications. In an effort to treat T1D, surgical techniques relative to transplant islets have been developed across histocompatability barriers [54]. Investigators have tried to address the issue of T1D through the use of stem cells and regenerative medicine [63]. These clinical trials have reported that autologous HSCs transplant together with high dose immunosuppression is able to induce complete remission (insulin independence) in most patients with early onset T1D [63]. Currently, autologous CB-SCs are under investigation in a clinical trial to treat T1D in children [64]. In one trial, 23 children have been treated, and 1 child treated in this protocol showed significant improvement in glucose control and was able to produce more insulin than children with similar prognosis [54]. Most of the recipients have reported enhanced blood glucose control and management, with retention of endogenous insulin production as assessed by stimulated C-peptide secretion. The mechanism of action is not yet known, but from this clinical trial is possible that infused CB-SCs may support both islet maintenance and regeneration as well as a resetting of the aberrant immune system by means of CB-SCs [54]. Recently, Haller MJ et al. [65] have reported, by using autologous CB-SCs therapies in an open-label phase I study, an interesting outcome relative the opportunity to improve T1D. In this clinical trial 15 recipients, affected by T1D and for whom autologous CB-SCs were harvested, have been submitted to a single intravenous infusion of autologous CB-SCs and the completed 1-year of post-infusion follow-up has been reported. No changes arisen in this trial as far as autoantibody titers, CD4-to-CD8 ratio, or other T-cell phenotypes, but an increase in CD4+CD25+FoxP3+ (Tregs) was evident after 6 months from the infusion [65]. No infusion-related adverse events has been reported together with someone of the finest associated metabolic indexes at 1 year post-infusion such as peak C-peptide which appeared to be higher than the historical controls, lacking the trial of a real control group [65].
Neurological disorders
These diseases are the third leading cause of death in the United States of America [66] Clinical trials were started with the purpose to evaluate CB-SCs differentiation ability in regenerating the injured neural tissue [54]. Briefly, the majority of clinical trials have suggested that administration of CB-SCs result in good degree of therapeutical benefit with no adverse events [66]. Therefore, some neuroprotective effects together with functional and behavioral improvements were evident and accompanied by decrease infiammatory cytokines and rescue/reduction of ischemic volume in case of vascular neurological disease [54]. A recent trial, in which the effect of CB-SCs in patients with spinal cord injuries were evaluated with the support of tomography and magnetic resonance imaging studies, showed that CB-SCs transplant improves sensory perception and mobility in thigh and hip regions through regeneration of the spinal cord [54].
Inherited biochemical disease
Hematopoietic stem cell transplantation is able to provide also non-hematopoietic cell regeneration or repair [58]. Starting from 2004, some trials have been performed in order to establish the suitability of CB-SCs in this type of diseases in comparison to bone barrow transplant as standard of care [58]. Worldwide clinical trials based on CB-SCs have showed that the quality of life, survival and co-morbidity of recipients have been improved. In this case a very important preliminary results is that through the use of CB-SCs also the exogenous enzyme replacement is possible thanks to the CB-SCs donor-derived enzyme-producing cells able to migrate across the blood-brain barrier and other organs [58].
