Expand human umbilical cord blood hematopoietic stem cells with PPAR-a agonists - Expand human umbilical cord blood hematopoietic stem cells with PPAR-a agonists
Abstract
Hematopoietic stem cells (HSCs) are defined by their self-renewal potential and ability to differentiate into
multiple blood lineages. Hematopoietic stem cell transplant (HSCT) is a mainstay of life-saving therapy for
hematopoietic malignancies and hypoproliferative disorders. The use of umbilical cord blood (UCB)-derived
HSCs provides many advantages over adult HSCs, including enhanced long-term immune recovery,
decreased graft versus host disease, and availability of donors from a broad population, expanding the
availability of HSCT for groups currently underrepresented in bone marrow registries. The use of haploidentical
transplants addresses many of these issues, but UCB would still be a highly useful resource if UCB units
contained sufficient numbers of HSCs. However, the low cell dose in most UCB units limits their use, as
insufficient HSCs leads to delayed engraftment, graft failure, and severe infectious complications. Even a
modest expansion of HSCs from UCB can solve many of these problems, and thus HSC expansion from UCB
has remained an important goal for the field.
Our goal is to use cryopreserved UCB from the NHLBI Biologic Biospecimen Repository to develop
new methods to expand functional HSCs for therapeutic applications. Recent studies have achieved ex
vivo expansion of HSCs using cytokine cocktails combined with small molecules, but these approaches require
exposure to high concentrations of cytokines. Cytokines induce differentiation and impair the self-renewal
function of primitive HSCs. HSC expansion with minimal cytokine exposure would therefore be ideal for clinical
applications. Our previous studies demonstrated a combination of two inhibitors (CHIR99021 and rapamycin)
maintains human and mouse long-term HSCs ex vivo in the absence of cytokines or serum. Based on this
finding, we performed a high throughput screen and identified several PPAR-a agonists, which are used
clinically to treat hypertriglyceridemia, that significantly expand long-term functional UCB HSC ex vivo while
minimizing exposure to cytokines. In this project, we will carry out studies to optimize and implement our
PPAR-a agonists-based expansion method using cryopreserved UCB stored in the NHLBI Biologic
Biospecimen Repository.
