Umbilical Cord Blood Hematopoietic Stem and Progenitor Cell Expansion for Therapeutic Use

Abstract

Hematopoietic stem cell transplantation (HSCT) is a potentially curative therapy for severe hematological malignancies and other severe disorders of the blood, immune system, and bone marrow. It is the most successful regenerative therapy to date, with 2013 marking the one millionth HSCT and the 25th anniversary of the irst umbilical cord blood (UCB) HSCT. UCB has most often been used for allogeneic HSCT when a matched bone marrow or peripheral blood donor is unavailable. Recently, novel genome editing technologies to correct inherited gene disorders or to modulate biomarkers/ receptors on HSC and the potential use of HSCT for a variety of other nonmalignant conditions have led to a surge of interest in autologous HSCT, with the HSC source depending on the condition to be treated. UCB HSCs may be used to generate red blood cells, granulocytes, or platelets ex vivo for transfusion into diicult-to-transfuse patients. Alternatively, UCB may be reprogrammed to induced pluripotent stem cells or used to generate cell lines, which can then be diferentiated into diferent cell lineages for transfusion or used as diagnostic reagents. Disadvantages of UCB are its restricted cell numbers and delayed hematological engraftment. Here, UCB HSC expansion/ manipulation ex vivo and clinical applications are addressed.

A modified CD34+ hematopoietic stem and progenitor cell isolation strategy from cryopreserved human umbilical cord blood

“…The first UCB HSCT was carried out just over 30 years ago using a matched sibling donor to treat a child with Fanconi anemia . The recipient remains alive and well.…”

“…Since then, over 40,000 unrelated donor UCB HSCTs have been conducted . UCB units may be banked for autologous, sibling (related), or allogeneic hematopoietic stem cell transplants, for both pediatric and adult patients . UCB is of particular importance as a source of hematopoietic stem cells for ethnic minorities, patients with rare human leukocyte antigen (HLA) types where unrelated matched donors cannot be found, or where the patient urgently requires a transplant and cannot wait for an adult donor .…”

“…UCB units may be banked for autologous, sibling (related), or allogeneic hematopoietic stem cell transplants, for both pediatric and adult patients . UCB is of particular importance as a source of hematopoietic stem cells for ethnic minorities, patients with rare human leukocyte antigen (HLA) types where unrelated matched donors cannot be found, or where the patient urgently requires a transplant and cannot wait for an adult donor . There are currently over 779,000 banked UCB units registered with the World Marrow Donor Association Search and Match registry across the world (https://statistics.wmda.info/).…”

“…There are currently over 779,000 banked UCB units registered with the World Marrow Donor Association Search and Match registry across the world (https://statistics.wmda.info/). Advantages of UCB over other cell sources for transplantation include the ease and noninvasive nature of collection, pretesting, and storage ahead of time; lower incidence of graft‐versus‐host disease even with less stringent HLA matching; and reports of increased graft‐versus‐leukemia effects . In contrast, disadvantages include limited cell numbers; lack of cells for second donor lymphocyte infusions; and slower or delayed engraftment of neutrophils, platelets, and immune cells …”

“…However, the sialomucin CD34 and the pentaspan transmembrane glycoprotein CD133 remain of key importance, with both being used in the preclinical and/or current good manufacturing practice (cGMP) clinical setting to enrich for human HSPCs from human UCB, bone marrow, and mobilized peripheral blood . By using magnetic bead separation technology, these hCD34 and hCD133 isolation procedures are relatively rapid and simple to use; can provide high purity, viability, and recovery rates; and can be used in a cGMP‐compliant manner . Their limitations relate to poorer HSPC recoveries, purity, and viability when starting with cryopreserved material …”