Umbilical cord blood and hematopoietic stem cells as treatment for anemia

People affected by anemia have a reduced capacity to carry oxygen because of anomalies or low quantity of hemoglobin in the blood. The main treatments for this condition are provided by changes in dietary habits, but transfusions and other aggressive measures are necessary in the most serious cases; the final therapy being bone marrow transplantation. This procedure is the only longterm solution that can restore normal hematopoiesis in Falconi anemia, in sickle cell disease and in
other forms of anemia characterised by hereditary disorders.

Interestingly, blood from umbilical cord (UCB) and placenta was used for the first time in 1998 for an allogeneic transplant to treat a five-year-old boy who suffered of Falconi anemia: cryopreserved umbilical-cord blood derived from the patient’s HLA identical newborn sister was thawed and infused. Before transplantation the marrow contained few or no detectable progenitor cells and 120 days after transplantation progenitors were at normal to supranormal frequencies.

The cellular repopulation was delayed compared to patients who have undergone transplantation with HLA-matched allogeneic bone marrow, probably because of the immaturity and less differentiation of hematopoietic stem and progenitor cells. Five months after transplantation the patient was discharged with normal clinical conditions and nine months after infusion he was leading a normal life without signs of GVHD.

This article allowed to extend umbilical cord blood as the source for bone marrow transplants in the following two decades.
Umbilical cord blood is now currently used also for sickle cell disease transplants because of the lower risk of graft-versus-host-disease (GVHD) which allows to transplant a partially HLAmismatched product.

Moreover, recent studies support the potential of ex-vivo expansion of cord stem cells using growth factors, prostaglandins or nicotinamide before infusion, although the best mix, the optimal concentration of the reagents and the best laboratory conditions are still unclear.

For example, co-culture of UCB units with MSCs and stimulatory cytokines has been shown to promote total nucleated cells and hematopoietic progenitor cells (HPC) expansion compared to the same cocktail containing only cytokines. In fact, it is thought that cell-to-cell contact promotes stem cell growth in addition to the presence of soluble growth factors.

Other enhancement strategies involve the manipulation of signaling pathways that promote cell expansion, in particular the Notch pathway seems to have an important regulatory role in the expansion and differentiation of human HPC. These ex-vivo enhancements can significantly improve the outcome of umbilical cord transplants since one of the main obstacles in using this source of stem cells is the limited number of HPC in a single UCB unit.

In the future, research should define numerous laboratory conditions to enhance transplantations, first of all defining the best subpopulations of UCB cells and the best molecular pathways for their expansion, maintenance and self-renewal. However, if we consider the tremendous improvements since 1998, when anemia was treated for the first time with this innovative therapy, we can only imagine where the future can lead us.

Q.-S. Zhang, Stem Cell Therapy for Fanconi Anemia, Boston, MA: Springer US, pp. 1–10. S. Shenoy, Umbilical Cord Blood : An Evolving Stem Cell Source for Sickle Cell Disease Transplants, STEM CELLS TRANSLATIONAL MEDICINE, 337–340 (2013).

P. Guardiola et al., Outcome of 69 allogeneic stem cell transplantations for Fanconi anemia using HLA-matched unrelated donors : a study on behalf of the European Group for Blood and Marrow Transplantation, Blood 95, no. 2, 422–430 (2017).

P. De Latour et al., Allogeneic hematopoietic stem cell transplantation in Fanconi anemia: the European Group for Blood and Marrow Transplantation experience, Blood 122, no. 4279–4286 (2013).

M. Norkin, H. M. Lazarus, and J. R. Wingard, Umbilical cord blood graft enhancement
strategies : has the time come to move these into the clinic ?, Bone Marrow Transplantation 48, no.
7, pp. 884–889 (2013).