Enhancing the efficacy of engraftment of cord blood for hematopoietic cell transplantation

Clinical cord blood (CB) hematopoietic cell transplantation (HCT) has progressed well since the initial successful CB HCT that saved the life of a young boy with Fanconi anemia. The recipient is alive and well now 28 years out since that first transplant with CB cells from his HLA-matched sister. CB HCT has now been used to treat over 35,000 patients with various malignant and non-malignant disorders mainly using HLA-matched or partially HLA-disparate allogeneic CB cells. There are advantages and disadvantages to using CB for HCT compared to other sources of transplantable hematopoietic stem (HSC) and progenitor (HPC) cells. One disadvantage of the use of CB as a source of transplantable HSC and HPC is the limited number of these cells in a single CB collected, and slower time to neutrophil, platelet and immune cell recovery. This review describes current attempts to: increase the collection of HSC/HPC from CB, enhance the homing of the infused cells, ex-vivo expand numbers of collected HSC/HPC and increase production of the infused CB cells that reach the marrow. The ultimate goal is to manipulate efficiency and efficacy for safe and economical use of single unit CB HCT

Impact of COVID-19 and Future Emerging Viruses on Hematopoietic Cell Transplantation and Other Cellular Therapies

COVID-19, where Co stands for corona, VI stands for virus, and D denotes disease, in the recent past referred to as 2019 novel coronavirus or 2019-nCoV, has impacted numerous lives and businesses, and has led to a surreal emergency state within world communities. COVID-19 and the future emergence of dangerous viruses will have strong and as yet possibly unanticipated consequences and impact on the present and future use of cellular therapies. In this commentary, we offer a dispassionate assessment of where we believe COVID-19, as well as future emerging viruses, might compromise successful cell transplantation (Fig. 1). These therapies include hematopoietic cell transplantation (HCT) using umbilical cord blood (CB), bone marrow (BM), and mobilized peripheral blood, which contain hematopoietic stem (HSC) and progenitor (HPC) cells, as well as various cellular populations involved in the emerging fields of reparative and regenerative medicine. Such cell populations include HSC, HPC, mesenchymal stem/stromal cells (MSC), and immune cells such as lymphocytes used in chimeric antigen receptor (CAR) T-cell therapies, as well as pluripotent stem cell–based therapies

Inhibiting HDAC for human hematopoietic stem cell expansion

In this issue of the JCI, Chaurasia and colleagues report an impressive ex vivo expansion of HSCs from human cord blood (CB) using cytokines and altering epigenetic modifications. The application of this protocol provides information that has potential for clinical consideration. The enhanced expansion of CB HSCs is a substantial advance over recent work from the Chaurasia and Hoffman group, in which ex vivo production of human erythroid progenitor cells from CB was promoted by chromatin modification. Moreover, this study takes advantage of information from the rapidly emerging, but not yet fully elucidated, field of epigenetics

Erythropoietin Surprises: An Immune Saga

Erythropoietin (EPO) an erythropoietic stimulating agent also exerts effects on other cell systems. Nairz et al. (2011) now link EPO and intracellular signaling through the EPO receptor (EPOR) to innate immune cell activity via macrophages

RHEX in the mix of erythropoietin signaling molecules

Comment on RHEX, a novel regulator of human erythroid progenitor cell expansion and erythroblast development. [J Exp Med. 201

Mechanism Unknown: Prostaglandin E2 May Improve HSC Therapies

A recent publication in Nature by North et al. (2007) has implicated the eicosanoid prostaglandin E2 in enhancement of hematopoietic stem cell function in zebrafish and in mice. This work may have practical therapeutic value, but much remains to be determined before this possibility is realized

Hypoxia Signaling Pathway in Stem Cell Regulation: Good and Evil

Purpose of Review: This review summarizes the role of hypoxia and hypoxia-inducible factors (HIFs) in the regulation of stem cell biology, specifically focusing on maintenance, differentiation, and stress responses in the context of several stem cell systems. Stem cells for different lineages/tissues reside in distinct niches, and are exposed to diverse oxygen concentrations. Recent studies have revealed the importance of the hypoxia signaling pathway for stem cell functions. Recent Findings: Hypoxia and HIFs contribute to maintenance of embryonic stem cells, generation of induced pluripotent stem cells, functionality of hematopoietic stem cells, and survival of leukemia stem cells. Harvest and collection of mouse bone marrow and human cord blood cells in ambient air results in fewer hematopoietic stem cells recovered due to the phenomenon of Extra PHysiologic Oxygen Shock/Stress (EPHOSS). Summary: Oxygen is an important factor in the stem cell microenvironment. Hypoxia signaling and HIFs play important roles in modeling cellular metabolism in both stem cells and niches to regulate stem cell biology, and represent an additional dimension that allows stem cells to maintain an undifferentiated status and multilineage differentiation potential

Inhibition of DPP4/CD26 and dmPGE2 treatment enhances engraftment of mouse bone marrow hematopoietic stem cells

Enhancing the engraftment of hematopoietic stem cells (HSC) is especially important when times to engraftment are prolonged due either to limiting numbers of HSC in the donor graft or to intrinsic slower engrafting time of the tissue sources of HSC. Both inhibition of Dipeptidylpeptidase (DPP) 4/CD26 and treatment of cells with 16,16 dimethyl prostaglandin E2 (dmPGE2) have been shown to enhance hematopoietic stem cell engraftment in murine transplantation models and have been evaluated in clinical settings for their influence on engraftment of cord blood cells, a tissue source of HSC known to manifest an extended time to engraftment of donor cells compared to that of bone marrow (BM) and mobilized peripheral blood for hematopoietic cell transplantation (HCT). Herein, we present new experimental data, using a CD45+ head-to head congenic model of donor mouse BM cells for engraftment of lethally-irradiated mice, demonstrating that similar levels of enhanced engraftment are detected by pulsing donor BM cells with Diprotin A, a DPP4 inhibitor, or with dmPGE2 prior to infusion, or by pretreating recipient mice with sitagliptin, also a DPP4 inhibitor, by oral gavage. Moreover, the combined effects of pretreating the donor BM cells with dmPGE2 in context of pretreating the recipient mice with sitagliptin after administration of a lethal dose of radiation resulted in significantly enhanced competitively repopulating HCT compared to either treatment alone. This information is highly relevant to the goal of enhancing engraftment in human clinical HCT

Hematopoietic Stem Cell Intracellular Levels of Ca2+ to the Rescue! What Next?

Calcium ions (Ca2+), ubiquitous signaling and second messenger molecules, are communicators for the transmission of messages in numerous cell functions. In this issue of Cell Stem Cell, Luchsinger et al. (2019) provide evidence through the use of transplantation and mechanistic studies for the finding that, “Harnessing Hematopoietic Stem Cell Low Intracellular Calcium Improves Their Maintenance In Vitro.