Advances in umbilical cord blood manipulation-from niche to bedside

Abstract

The use of umbilical cord blood (UCB) as an alternative haematopoietic cell source in lieu of bone marrow for haematopoietic reconstitution is increasingly becoming a mainstay treatment for both malignant and nonmalignant diseases, as most individuals will have at least one available, suitably HLA-matched unit of blood. The principal limitation of UCB is the low and finite number of haematopoietic stem and progenitor cells (HSPC) relative to the number found in a typical bone marrow or mobilized peripheral blood allograft, which leads to prolonged engraftment times. In an attempt to overcome this obstacle, strategies that are often based on native processes occurring in the bone marrow microenvironment or 'niche' have been developed with the goal of accelerating UCB engraftment. In broad terms, the two main approaches have been either to expand UCB HSPC ex vivo before transplantation, or to modulate HSPC functionality to increase the efficiency of HSPC homing to the bone marrow niche after transplant both of which enhance the biological activities of the engrafted HSPC. Several early phase clinical trials of these approaches have reported promising results.

Figure 1

Median times to neutrophil engraftment of mobilized PBSC, unrelated donor marrow and single UCB transplants after a myeloablative preparative regimen (transplant is on day 0). Engraftment is most often defined as an absolute neutrophil count >500 cells per μl for three consecutive days. The range is indicated by the orange box, with a line at the median. Abbreviations: PBSC, peripheral blood stem cells; UCB, umbilical cord blood.

Figure 2

Activities of HSPC required for successful umbilical cord blood engraftment. HSPC home toward the bone marrow (1), expand within the bone-marrow microenvironment (2) and differentiate into mature cell lineages (3). Listed below each activity are the mediators that have been used in strategies to modulate UCB engraftment. Note that MSC are present in the marrow ‘niche’ and perhaps also take a de novo form as perivascular cells. Abbreviations: DLL1, Delta-like ligand; G-CSF; granulocyte colony-stimulating factor; GM-CSF; granulocyte–macrophage colony-stimulating factor; HSPC, haematopoietic stem and progenitor cells; MSC, mesenchymal stromal cells; PGE₂, prostaglandin E2; SCF, stem cell factor; SDF-1, stromal cell-derived factor-1; TEPA, tetra-ethylenepentamine; TPO, thrombopoietin.

Figure 3

General schema of a double UCB transplant platform. Before transplant, one UCB unit is thawed and manipulated by either priming with an agent to affect homing on the day of transplant (1–2 h) or expanded for 7– 21 days before transplantation. In the two most-recent trials of UCB expansion, one UCB unit will be thawed, followed by positive selection of the HSPC of interest (AC133⁺ or CD34⁺ cells) and subsequently expanded with nicotinamide or SR1, respectively, for 21 days. The unselected AC133^– or CD34^– cell fraction is re-cryopreserved. After 5 days of preparative chemotherapy (typically), the unmanipulated UCB unit is infused, followed by the expanded UCB unit and then the thawed ‘unselected’ cells. Abbreviations: HSPC, haematopoietic stem and progenitor cells; UCB, umbilical cord blood.

Figure 4

UCB manipulation offers improved time to neutrophil engraftment. Shown are the median times to neutrophil recovery from published clinical trials testing UCB manipulation involving expansion mediated by MSC, TEPA, Notch and cytokines, and priming of UCB by C3a, PGE₂ and sitagliptin. Note that the trials of factors in red text were performed in patients receiving a reduced intensity conditioning regimen, whereas those in black text were performed in myeloablated patients. Abbreviations: MSC, mesenchymal stromal cells; PBSC, peripheral blood stem cells; PGE₂, prostaglandin E2; TEPA, tetra-ethylenepentamine; UCB, umbilical cord blood.