**6. Conclusions**

The key considerations in expanding human UCB HSC include (i) cost to health providers of GMP cell products and clinical trials, (ii) the number of clinical trials that UCB recipients can be entered into and alternative protocols for HSCT, (iii) restrictions in the use of some compounds or protocols related to intellectual property rights, (iv) defining which UCB units will engraft long term and why 1 UCB unit will engraft in preference to another, (v) addressing variability in donor cell response, particularly related to platelet engraftment and long-term reconstitution of the expanded UCB unit, (vi) the availability of licensed facilities in which to expand cells, and (vii) the optimal development of the best and cheapest protocols to allow rapid engraftment of neutrophils and platelets, longer-term lymphoid reconstitution, and expansion of the HSCs without their differentiation for long-term hemopoietic reconstitution at affordable costs to the healthcare provider and for transplant recipients.

Clinical trials to date have demonstrated improved homing or retention in the bone marrow niche and improved early neutrophil engraftment. Further research and development is required to regulate the self-renewal of the HSC without significant differentiation in order to facilitate novel genome engineering studies and the development of this into a cost-effective GMP-grade process. Ensuring that the cells can effectively home to and engraft in the bone marrow after this manipulation may require the addition of small molecules (e.g., fucTVI, dmPGE2) for a short period prior to transplant after expansion with specific growth factor cocktails. In the short term, better characterization and refinement of newer and existing UCB products will result in shorter hospital stays and improved prognosis for HSC transplant recipients as to-time-to-hematological-reconstitution shortens, the incidence of graft failure reduces and treatment of residual malignant or cure for acquired or inherited disease improves. Better characterization of UCB self-renewal and differentiation should also expand the treatment choices available and will be a valuable resource to patients in ethnic minority and other groups where it can be difficult to find a matched graft or where graft engineering and genome editing offer the best choice for a cure. In the longer term, a full understanding of the molecular mechanisms that govern HSC commitment and differentiation, the homing of HSCs to bone marrow, and the control, retention, and engraftment of normal HSCs within the specialized bone marrow niches will lead to achievable and cost effective translation of a great deal of research into effective clinical practice for many millions of individuals worldwide.
