Abstract
Umbilical cord blood (UCB) is a promising source of stem cells to use in early haematopoietic stem cell transplantation (HSCT) approaches for several genetic diseases that can be diagnosed at birth. Mucopolysaccharidosis type I (MPS-I) is a progressive multi-system disorder caused by deficiency of lysosomal enzyme α-L-iduronidase, and patients treated with allogeneic HSCT at the onset have improved outcome, suggesting to administer such therapy as early as possible. Given that the best characterized MPS-I murine model is an immunocompetent mouse, we here developed a transplantation system based on murine UCB. With the final aim of testing the therapeutic efficacy of UCB in MPS-I mice transplanted at birth, we first defined the features of murine UCB cells and demonstrated that they are capable of multi-lineage haematopoietic repopulation of myeloablated adult mice similarly to bone marrow cells. We then assessed the effectiveness of murine UCB cells transplantation in busulfan-conditioned newborn MPS-I mice. Twenty weeks after treatment, iduronidase activity was increased in visceral organs of MPS-I animals, glycosaminoglycans storage was reduced, and skeletal phenotype was ameliorated. This study explores a potential therapy for MPS-I at a very early stage in life and represents a novel model to test UCB-based transplantation approaches for various diseases.
Highlights
Umbilical cord blood (UCB) is a promising source of stem cells to use in early haematopoietic stem cell transplantation (HSCT) approaches for several genetic diseases that can be diagnosed at birth
Building upon the data from our previous study where we observed that the transplantion of normal bone marrow (BM) into newborn Mucopolysaccharidosis type I (MPS-I) mice, soon after the placental protection, can prevent GAGs accumulation in multiple organs and the distinctive skeletal dysplasia[28], in this study we provide an extensive description of murine UCB cells (UCBCs) features, in comparison with adult BM cells (BMCs)
Regarding the haematopoietic stem cells (HSCs) subset detectable within adult BMCs by Lin−Sca-1+c-kit+ (LSK) staining, in UCBCs specimens there was a reduced proportion of LSK cells (Fig. 1B)
Summary
Umbilical cord blood (UCB) is a promising source of stem cells to use in early haematopoietic stem cell transplantation (HSCT) approaches for several genetic diseases that can be diagnosed at birth. The availability of cells to transplant is more rapid, thanks to the augmented probability to find HLA-matched donors and the existence of cord blood banks where UCB units are stored frozen and ready to use This factor is of primary importance because in many IEMs the timing of the treatment has a strong impact on patient outcome. Clinical and preclinical evidences attest that the precociousness of the treatment is critical to prevent long-term pathological consequences[20] For this reason, we tested an UCBT approach at early age in MPS-I murine model[10], to investigate a novel and promising therapeutic strategy. Attempts to mimic UCBT have been made with either fetal liver cells, blood or BM collected from mouse fetuses during the last third of pregnancy, or newborn blood[21,22,23,24,25,26,27], but, to our knowledge, no published data exists about the transplantation of murine UCB into newborn recipients, in particular in a mouse model of disease attesting a clinical correction
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