History

The origins of the field of cord blood (CB) hematopoietic cell transplantation (HCT) have been previously reviewed [1-3]. In short, it started with our work that determined that numbers of hematopoietic progenitor cells (HPCs) in single CB unit collections were within the range of those numbers of HPCs that were associated with successful bone marrow (BM) HCT, and that it was possible to successfully freeze/cryopreserve and then have high efficiency recovery of the frozen hematopoietic stem cells (HSCs)/HPCs [4]. We now know that these cells can be retrieved at high efficiency after more than 23 years [5]. This original work [4] led to the first proof-of-principle CB bank in the author’s laboratory that assessed the content of HPCs within CB units sent from a distant obstetrical unit, and then froze the cells for use for HLA-matched sibling CB transplants [6]. The scientific paper that led to the first CB transplant was a collaborative national effort [4], and the first CB transplant itself, performed in Paris, France, with cells collected in Durham, NC, and sent to our laboratory for assessment and freezing prior to hand-delivery to the Hopital St Louis in Paris, was an international collaborative effort [6]. The first recipient of the CB transplant in October 1988 in Paris is still alive and well. Cryopreserved CB units from the first CB bank in my laboratory were then used for the next four CB transplants in Paris (n = 2), Baltimore and Cincinnati, as well as two more of the next five transplants [7-9].

The field of CB HCT has come a long way since these initial laboratory research and clinical efforts in terms of the transplants themselves [1,2] and our much-improved understanding of the biology of HSCs and HPCs and their regulation [10-12]. CB HCTs went from HLA-matched sibling transplants to partially matched related, and then to HLA-matched or partially HLA-disparate unrelated CB transplants. There have been more than 40,000 CB HCTs performed since our initial efforts, which have now treated a large variety of malignant and non-malignant disorders [1,2,13,14]. While there are many advantages to use of CB, versus either BM- or mobilized peripheral blood for transplantation, including ready availability of the units and lower levels of acute graft-versus-host disease, there are concerning disadvantages to the use of CB that have limited its use. These include slower time to neutrophil, platelet and immune cell recovery. Because of the low numbers of HSCs and HPCs in single collections of CB, clinical efforts moved to use of double CB unit transplants, which helped move the field to greater use of CB HCT for adults [15-17]. Double CB HCT was also utilized for children although there is currently no evidence to date that the time to engraftment is any faster with double compared to single CB HCTs for either adults or children [15-19]. Haploidentical (haplo) transplants [20-23] have recently competed with CB as a source of transplantable cells for HCT. The engraftment of haplo-transplants is more rapid than CB, and the use of haplo HCT may have an up-front economic advantage, regarding less monetary cost. However, the relapse rates after haplo transplants may be higher than with CB HCT, so it remains to be determined how in actuality haplo-HCT compares to that of CB HCT in terms of overall patient benefit, including relapse and survival rates of the patients, and the long-term costs of the transplant for society. Some investigators have begun using haplo-transplants in combination with a CB unit in order to elicit a more rapid up-front engraftment using haplo cells, with the longer-term engraftment apparently being mediated from the CB unit [24-25]. This combination of both a haplo and a CB unit for HCT has interesting possibilities, but it may be that scientific advances in the near future will obviate the need for this combination cell therapy, perhaps resulting in a single unit CB HCT eventually becoming the cell type of choice for all HCTs for a number of reasons, including economical ones. Efforts to counter the disadvantages of single unit CB HCT are currently underway in a number of research laboratories, and these efforts are covered in this review, along with a perspective on future efforts.

Laboratory & clinical efforts to enhance CB HCT

The goals are to collect more highly potent HCSs and HPCs in single CB units, to effectively expand the collected cells and/or to enhance the homing efficiency of these cells so that they more efficiently travel to BM microenvironment niches, where they must reach for nurturing of the engrafted cells for both rapid and sustained long-term engraftment. Once in the BM, stromal-cell– and cytokine/chemokine–HSC/HPC interactions influence the self-renewal, survival, proliferation and differentiation capacities of the HSCs and HPCs [10-12]. Ultimately what is needed is the most efficient and cost-effective means to enhance single unit CB HCT. At best, this will entail the simplest procedures that can be carried out at any, and not just at selected, CB collection and transplant centers.

Enhancing CB HSC collections

Most transplant centers request the largest CB collection available in CB banks for the closest donor HLA match to the recipient. It is left up to the staff where the CB collections are made to maximize the volume of CB collected. Recently, the American College of Obstetricians and Gynecologists released a position statement on delayed CB clamping that recommended an interval of 30–60 seconds after delivery of healthy term babies (see Cord Blood Association website), which means that a lesser volume of CB will be collected, which in turn means that fewer HSCs and HPCs will be present in the collected CB units. However, there are still ways to enhance the collection of HSCs even if clamping is delayed. One way that was tried in the laboratory previously is to perfuse the CB once the cord is separated from the body. This does result in collections of increased volumes of CB with increased numbers of HSCs and HPCs [26]. However, this is a cumbersome procedure that is not likely to find widespread use in collection centers, and has not been used for units stored in either unrelated or family (private) CB banks. Another more recent innovation from the author’s laboratory that has resulted in obtaining 2–5-fold more HSCs/unit of CB collected is the collection and processing of cells in hypoxic (e.g., 3%) O₂ tensions [27,28], which is more closely related to the oxygen tension of the cells within the body (with O₂ tensions in the bone marrow being in the range of 1 and 5%, and CB being less than 10%, compared to collections of cells in ambient air of ~21%). This hypoxic collection/processing of the cells prevents the ambient air induced loss of HSCs through a phenomenon we termed extra physiological oxygen shock/stress (EPHOSS), which causes the very rapid differentiation, rather than cell death, of a large proportion of HSCs in the CB upon short-term exposure to ambient air [27]. Thus, CB collected and processed in ambient air has fewer HSCs and more HPCs, and the HPCs are in rapid cell cycle. By contrast, CB collected/processed in 3% O₂ have more HSCs, but fewer HPCs, and these HPCs are in a slow or non-cycling state. EPHOSS is mediated through an intracellular networking axis that involves at the least tumor suppressor p53, the mitochondrial permeability transition pore (MPTP) and cyclophilin D, with hypoxia inducing factor (HIF)-1α, and the hypoxamir, miR210 playing a role. Upon sensing ambient air O₂ levels, the MPTP in cells open up with resultant release of reactive oxygen species (ROS), which induce HSCs to differentiate into HPCs. While countering EPHOSS by the hypoxic collection/processing could obviate problems with limiting HSC numbers in single CB collections, it is not a procedure that lends itself to routine use at CB collection centers. In alternative efforts to block EPHOSS induced differentiation, we found that if CB is collected/processed in air but in the continued presence of cyclosporine A (CsA), which maintains the MPTP in a closed position and reduces release of ROS from the mitochondria, one can collect more HSCs [27]. CsA would certainly be easier to use at CB collection centers since this obviates the need for collection of cells in an hypoxic chamber, but such procedures are not without problems. CsA is not easy to use, the best concentrations of CsA to use for each procedure needs to be worked out, and may vary with the lot of CsA obtained. Also, CsA is toxic to cells upon prolonged exposure, so it is clear that other means are needed to prevent EPHOSS [27,28]. We are currently working on such other procedures, including the evaluation of small molecule inhibitors of epigenetics and autophagy/mitophagy, amongst a number of other means alone or in combination.

Ex vivo expansion of CB HSCs & HPCs

Efforts to ex vivo expand numbers of HSCs and HPCs have been ongoing for more than 30 years, and most recently a number of small molecules have been used to ex vivo expand these cells in CB. SR1 has been effectively used in the laboratory [29], and has shown promise for clinical translation [30]. UM171, is a small molecule that in laboratory studies appears more potent than SR1 [31]. Clinical trials with UM171 are ongoing, with clinical efficacy yet to be reported. Both SR1 and UM171 are not by themselves effective, but require addition of selected cytokines for their potent ex vivo expansion effects [29-31]. Clinical studies have been reported using Notch Ligand [32] and nicotinamide induced ex vivo expansion of CB [33]. The known mechanisms for these procedures have been elucidated in the individual papers, but it is clear that complete mechanistic insight into how these agents work is yet to be fully elucidated. Greater insight into how facets of HSC/HPC self-renewal, proliferation, survival and differentiation are mediated will no doubt provide added efficacy for these procedures. Other pre-clinical studies have also evaluated ex vivo expansion methods [34-36]. It remains to be determined which procedures will eventually be used on a larger scale, and if in fact such procedures will be cost effective, as they clearly will add costs to CB HCT, which already include the cost of the CB units themselves and the transplantation procedure. Our lab has also worked on means to expand CB HSCs and HPCs using Oct4 activators [37] or cytokines plus inhibition of the enzyme Dipeptidylpeptidase (DPP) 4 [38], with additional efforts in progress, including modulating glucose metabolism. Whether or not ex vivo expansion will eventually be used as a routine effort is currently not clear. It most likely will be performed in selected laboratories and by companies. Regardless, we will clearly learn much about how HSCs and HPCs are regulated, with the possibility that this information can in the future be used efficaciously to modulate the production and differentiation of these cells in vivo for quicker and more sustained engraftment of neutrophils, platelets and immune cells. It may actually be that the future of enhancing the efficacy of CB HCT lies in the in vivo, rather than ex vivo, expansion and subsequent differentiation of the engrafted cells and this is an area of research that requires intense investigation.

Enhancing the homing capacities of HSCs

It may be that either or both of the enhanced collection of HSCs by blocking EPHOSS, or ex vivo expansion of these HSCs and HPCs can be made more effective for CB HCT by modulating the capacity of these donor cells to better home to the BM once they are injected into the recipients. There have been a number of efforts to enhance the homing capabilities of HSCs. These include: short term ex vivo enforced fucosylation of the cells [39-41], prostaglandin (PG) E pretreatment [42-44], inhibition of the enzyme DPP4 with small molecule inhibitors [38,45] or hyperthermia [46]. Perhaps using combinations of these pretreatment procedures may even further enhance the homing efficiency of ex vivo treated cells prior to their intravenous infusion.

CXCR4 is a receptor that binds and responds to the chemokine, stromal cell derived factor (SDF)-1/CXCL12. The SDF-1/CXCL12-CXCR4 axis has been implicated in chemotaxis, migration, survival and homing of HSCs, HPCs and other cell types [47]. DPP4 is found within many cell types and is present on the cell surface as CD26 [48]. It is also found in serum and plasma, and can truncate SDF-1/CXCL12 by removing the first two N-terminal amino acids where the second amino acid is usually an alanine or a proline. DPP4 truncated SDF-1/CXCL12 is much less active as a chemotactic and survival factor than its own full length form, and the truncated form blocks the activity of the full length chemokine [38,45,48]. Inhibiting DPP4 with small molecules such as the tripeptide Diprotin A (ILE-PRO-ILE), or sitagliptin (which is a DPP4 inhibitor used to treat Type 2 diabetes), enhances the activity of SDF-1/CXCL12 as well as other proteins (such as granulocyte macrophage [GM] colony stimulating factor [CSF], G-CSF, interleukin [IL]-3, and erythropoietin [EPO], which are amongst a large number of biologically active proteins that have DPP4 truncation sites) [49,50]. Deletion of the dpp4 gene or inhibiting dpp4 activity accelerates recovery of hematopoiesis in mice from stresses such as sub-lethal doses of radiation or chemotherapeutic drugs [38]. Moreover, treating end-stage patients with leukemic or lymphoma with short term administration of orally active sitagliptin once a day for 4 days starting 1 day before administration of the CB graft has accelerated time to neutrophil engraftment after single unit CB HCT to a median of 21 days [51,52], and more recent clinical studies adjusting the sitagliptin administration to twice a day for 4 days has significantly shortened the time to neutrophil engraftment to a median of about 19 days [Farag and Broxmeyer, submitted for publication]. Another means to enhance engraftment is to place the recipients in a hyperbaric chamber prior to CB infusion in order to decrease O₂, as EPO has a negative effect on the chemotaxis and homing of HSCs and HPCs [53]. We recently found that a screen of small-molecule compounds identified glucocorticoid (GC) hormone signaling as an activator of the expression of the chemokine receptor CXCR4 in human CB HSCs and HPCs, short-term pretreatment of these cells with GSs (Dexamethasone, Flonase, cortisol, Medrol) promoted the SDF-1/CXCL12-axis mediated chemotaxis, homing, and long-term engraftment when CB CD34+ cells were transplanted into primary- and secondary-sublethally irradiated NSG immune-deficient mice. Mechanistically, the activated glucocorticoid receptor binds directly to a glucocorticoid response element in the CXCR4 promoter and recruits the SRC-1-p300 complex to promote H4K5 and H4K16 histone acetylation, thereby facilitating transcription of CXCR4 [54].

Future perspectives for CB HCT

It is clear that if the field of CB HCT is to be sustained, and more importantly to progress, additional laboratory and clinical efforts are needed. The laboratory and clinical investigators must work together to make enhancement of CB HCT a reality. This is a very important goal that can be realized, but this author is convinced that whatever is done in order to sustain the field should be simple and cost effective. I envision a time in the near future when higher numbers of more potent HSCs will be able to be routinely collected through blocking EPHOSS or other like efforts, for example collecting cells in ambient air with DPP4 inhibition also results in EPHOSS-like protective effects with enhanced numbers of HSCs [38], but through a different mechanism than we reported for EPHOSS protection [Unpublished observations]. The potency of the cells can be assessed by limiting dilution of cells in colony assays in vitro or engraftment in vivo into sub-lethally irradiated immune-deficient mice [27], and perhaps by chemical potency assays [55]. The cells will perhaps be expanded, although ex vivo expansion may not be needed if the collections contain enough increased HSCs. These cells could then be either pretreated for a few hours ex vivo to enhance their engraftment (by fucosylation, PGE, DPP4 inhibition, hyperthermia glucocorticoid stimulation, or combinations of these short-term treatments) and then infused into recipients who may be additionally pretreated to enhance self-renewal and/or differentiation of the infused cells (e.g., by DPP4 inhibition and/or by preconditioning in a hyperbaric chamber). Animal models have already shown that a combination of PGE pretreatment of cells followed by injection of these cells into hosts treated with sitagliptin (a DPP4 inhibitor) results in improved engraftment above that of either procedure itself [56]. So there is already experimental precedence for at least one possibly easily used combination procedure.

Table 1 provides the various strategies that can be considered for enhancement of CB HCT beyond that of the usual currently used method of collection/processing in air without further manipulations. Any one, or combinations, of the procedures shown should allow for enhanced CB HCT. It is likely that simple and uncomplicated procedures that can be performed most cost effectively in many, not just selected, collection and transplant centers will have the most sustained beneficial effects on enhancing the efficacy of CB HCT. It is only with efforts such as these, or newer efforts to be determined, that the field of CB HCT will continue to move forward. It is up to laboratory and clinical investigators working together to make this envisioned future a reality.

Financial and competing interests disclosure

Hal E Broxmeyer is on the Medical Scientific Advisory Board of Cord:Use, a cord blood banking company. No writing assistance was utilized in the production of this manuscript.

References

1. Broxmeyer HE, Farag SS, Rocha V. Cord blood hematopoietic cell transplantation. In: Forman SJ, Negrin RS, Antin JH, Appelbaum FR, editors. Thomas’ Hematopoietic Cell Transplantation, 5th Ed. Oxford, England: John Wiley & Sons, Ltd; 2016, 437–55. CrossRef

2. Ballen KK, Gluckman E, Broxmeyer HE. Umbilical Cord Blood Transplantation – The First 25 Years And Beyond. 2013; 491–8. DOI

3. Broxmeyer HE. Enhancing the efficacy of engraftment of cord blood for hematopoietic cell transplantation. Transfus. Apher. Sci. 2016; 364–72. DOI

4. Broxmeyer HE, Douglas GW, Hangoc G et al. Human umbilical cord blood as a potential source of transplantable hematopoietic stem/progenitor cells. Proc. Natl Acad. Sci. USA 1989; 3828–32. CrossRef

5. Broxmeyer HE, Lee MR, Hangoc G et al. Hematopoietic stem/progenitor cells, generation of induced pluripotent stem cells, and isolation of endothelial progenitors from 21- to 23.5-year cryopreserved cord blood. Blood 2011; 4773–7.
CrossRef

6. Gluckman E, Broxmeyer HA, Auerbach AD et al. Hematopoietic reconstitution in a patient with Fanconi’s anemia by means of umbilical-cord blood from an HLA-identical sibling. N. Engl. J. Med. 1989; 1174–8. CrossRef

7. Wagner JE, Broxmeyer HE, Byrd RL et al. Transplantation of umbilical cord blood after myeloablative therapy: analysis of engraftment. Blood 1992; 1874–81. Webiste

8. Kohli-Kumar M, Shahidi NT, Broxmeyer HE et al. Haemopoietic stem/progenitor cell transplant in Fanconi anaemia using HLA-matched sibling umbilical cord blood cells. Br. J. Haematol. 1993; 419–22. CrossRef

9. Broxmeyer HE, Gluckman E, Auerbach A et al. Human umbilical cord blood: a clinically useful source of transplantable hematopoietic stem/progenitor cells. Int. J. Cell Cloning 1990; Suppl. 1: 76–89. CrossRef

10. Shaheen M, Broxmeyer HE. The humoral regulation of hematopoiesis. In: Hoffman R, Benz EJ Jr, Shattil SJ et al. editors. Hematology: Basic Principles and Practice, 5th Ed. Philadelphia, PA: Elsevier Churchill Livingston; 2009, 253–75.

11. Shaheen M, Broxmeyer HE. Hematopoietic cytokines and growth factors. In: Broxmeyer HE, editor. Cord Blood Biology, Transplantation, Banking, and Regulation. Bethesda, MD: AABB Press; 2011, 35–74.

12. Shaheen M, Broxmeyer HE. Principles of cytokine signaling. In: Hoffman R, Jr, Benz EJ, Silberstein LE, Heslop H, Weitz JI, Anastasi J, editors. Hematology: Basic Principles and Practice, 6th Ed. Philadelphia, PA: Elsevier Saunders; 2013, 136–46.

13. Rocha V. Umbilical cord blood cells from unrelated donor as an alternative source of hematopoietic stem cells for transplantation in children and adults. Semin. Hematol. 2016; 237–45. CrossRef

14. Milano F, Gooley T, Wood B et al. Cord-Blood Transplantation in Patients with Minimal Residual Disease. N. Engl. J. Med. 2016; 944–53. CrossRef

15. Barker JN, Weisdorf DJ, DeFor TE et al. Transplantation of 2 partially HLA-matched umbilical cord blood units to enhance engraftment in adults with hematologic malignancy. Blood 2005; 1343–7. DOI

16. Scaradavou A, Brunstein CG, Eapen M et al. Double unit grafts successfully extend the application of umbilical cord blood transplantation in adults with acute leukemia. Blood 2013; 752–8. CrossRef

17. Wagner JE, Jr., Eapen M, Carter S et al. One-unit versus two-unit cord-blood transplantation for hematologic cancers. N. Engl. J. Med. 2014; 1685–94. CrossRef

18. Michel G, Galambrun C, Sirvent A et al. Single- vs double-unit cord blood transplantation for children and young adults with acute leukemia or myelodysplastic syndrome. Blood 2016; 3450–7. CrossRef

19. Tsang KS, Leung AW, Lee V et al. Indiscernible Benefit of Double-Unit Umbilical Cord Blood Transplantation in Children: A Single-Center Experience From Hong Kong. Cell Transplant. 2016; 1277–86. CrossRef

20. Mancusi A, Ruggeri L, Velardi A. Haploidentical hematopoietic transplantation for the cure of leukemia: from its biology to clinical translation. Blood 2016; 2616–23. CrossRef

21. Robinson TM, O’Donnell PV, Fuchs EJ, Luznik L. Haploidentical bone marrow and stem cell transplantation: experience with post-transplantation cyclophosphamide. Semin. Hematol. 2016; 90–7. CrossRef

22. Martelli MF, Aversa F. Haploidentical transplants using ex vivo T-cell depletion. Semin. Hematol. 2016; 252–6.
CrossRef

23. McCurdy SR, Fuchs EJ. Selecting the best haploidentical donor. Semin. Hematol. 2016; 246–51. CrossRef

24. van Besien K, Childs R. Haploidentical cord transplantation – The best of both worlds. Semin. Hematol. 2016; 257–66. CrossRef

25. van Besien K, Hari P, Zhang MJ et al. Reduced intensity haplo plus single cord transplant compared to double cord transplant: improved engraftment and graft-versus-host disease-free, relapse-free survival. Haematologica 2016; 634–43. CrossRef

26. Broxmeyer HE, Cooper S, Hass DM, Hathaway JK, Stehman FB, Hangoc G. Experimental basis of cord blood transplantation. Bone Marrow Transplant. 2009; 627–33. CrossRef

27. Mantel CR, O’Leary HA, Chitteti BR et al. Enhancing Hematopoietic Stem Cell Transplantation Efficacy by Mitigating Oxygen Shock. Cell 2015; 1553–65. CrossRef

28. Broxmeyer HE, O’Leary HA, Huang X, Mantel C. The importance of hypoxia and extra physiologic oxygen shock/stress for collection and processing of stem and progenitor cells to understand true physiology/pathology of these cells ex vivo. Curr. Opin. Hematol. 2015; 273–78. CrossRef

29. Boitano AE, Wang J, Romeo R et al. Aryl hydrocarbon receptor antagonists promote the expansion of human hematopoietic stem cells. Science 2010; 1345–8. CrossRef

30. Wagner JE, Jr., Brunstein CG, Boitano AE et al. Phase I/II Trial of StemRegenin-1 Expanded Umbilical Cord Blood Hematopoietic Stem Cells Supports Testing as a Stand-Alone Graft. Cell Stem Cell 2016; 144–55. CrossRef

31. Fares I, Chagraoui J, Gareau Y et al. Cord blood expansion. Pyrimidoindole derivatives are agonists of human hematopoietic stem cell self-renewal. Science 2014; 1509–12. CrossRef

32. Delaney C, Heimfeld S, Brashem-Stein C, Voorhies H, Manger R, Bernstein ID. Notch-mediated expansion of human cord blood progenitor cells capable of rapid myeloid reconstitution. Nat. Med. 2010; 232–6. CrossRef

33. Horwitz ME, Chao NJ, Rizzieri DA et al. Umbilical cord blood expansion with nicotinamide provides long-term multilineage engraftment. J. Clin. Invest. 2014; 3121–8. CrossRef

34. Chaurasia P, Gajzer DC, Schaniel C, D’Souza S, Hoffman R. Epigenetic reprogramming induces the expansion of cord blood stem cells. J. Clin. Invest. 2014; 2378–95. CrossRef

35. de LM, McMannis J, Gee A et al. Transplantation of ex vivo expanded cord blood cells using the copper chelator tetraethylenepentamine: a phase I/II clinical trial. Bone Marrow Transplant. 2008; 771–8. DOI

36. de LM, McNiece I, Robinson SN et al. Cord-blood engraftment with ex vivo mesenchymal-cell coculture. N. Engl. J. Med. 2012; 2305–15. DOI

37. Huang X, Lee MR, Cooper S et al. Activation of OCT4 enhances ex vivo expansion of human cord blood hematopoietic stem and progenitor cells by regulating HOXB4 expression. Leukemia 2016; 144–53. CrossRef

38. Broxmeyer HE, Hoggatt J, O’Leary HA et al. Dipeptidylpeptidase 4 negatively regulates colony-stimulating factor activity and stress hematopoiesis. Nat. Med. 2012; 1786–96. CrossRef

39. Xia L, McDaniel JM, Yago T, Doeden A, McEver RP. Surface fucosylation of human cord blood cells augments binding to P-selectin and E-selectin and enhances engraftment in bone marrow. Blood 2004; 3091–6. CrossRef

40. Popat U, Mehta RS, Rezvani K et al. Enforced fucosylation of cord blood hematopoietic cells accelerates neutrophil and platelet engraftment after transplantation. Blood 2015; 2885–92. CrossRef

41. Robinson SN, Thomas MW, Simmons PJ et al. Non-fucosylated CB CD34+ cells represent a good target for enforced fucosylation to improve engraftment following cord blood transplantation. Cytotherapy 2017; 285–92. CrossRef

42. North TE, Goessling W, Walkley CR et al. Prostaglandin E2 regulates vertebrate haematopoietic stem cell homeostasis. Nature 2007; 1007–11. CrossRef

43. Hoggatt J, Singh P, Sampath J, Pelus LM. Prostaglandin E2 enhances hematopoietic stem cell homing, survival, and proliferation. Blood 2009; 5444–55. CrossRef

44. Cutler C, Multani P, Robbins D et al. Prostaglandin-modulated umbilical cord blood hematopoietic stem cell transplantation. Blood 2013; 3074–81. CrossRef

45. Christopherson KW, Hangoc G, Mantel CR, Broxmeyer HE. Modulation of hematopoietic stem cell homing and engraftment by CD26. Science 2004; 1000–3. CrossRef

46. Capitano ML, Hangoc G, Cooper S, Broxmeyer HE. Mild Heat Treatment Primes Human CD34(+) Cord Blood Cells for Migration Toward SDF-1alpha and Enhances Engraftment in an NSG Mouse Model. Stem Cells 2015; 1975–84. CrossRef

47. Capitano ML & Broxmeyer HE. CXCL12/SDF-1 and hematopoiesis, reference module. In: Bradshaw RA, Stahl PD, editors. Biomedical Sciences, Encyclopedia of Cell Biology, Vol. 3. 2016, 624–31. CrossRef

48. Christopherson KW, Hangoc G, Broxmeyer HE. Cell surface peptidase CD26/dipeptidylpeptidase IV regulates CXCL12/stromal cell-derived factor-1 alpha-mediated chemotaxis of human cord blood CD34+ progenitor cells. J. Immunol. 2002; 7000–8. CrossRef

49. Ou X, O’Leary HA, Broxmeyer HE. Implications of DPP4 modification of proteins that regulate stem/progenitor and more mature cell types. Blood 2013; 161–9. CrossRef

50. O’Leary H, Ou X, Broxmeyer HE. The role of dipeptidyl peptidase 4 in hematopoiesis and transplantation. Curr. Opin. Hematol. 2013; 314–9. CrossRef

51. Farag SS, Srivastava S, Messina-Graham S et al. In vivo DPP-4 inhibition to enhance engraftment of single-unit cord blood transplants in adults with hematological malignancies. Stem Cells Dev. 2013; 1007–15. CrossRef

52. Velez de MN, Strother RM, Farag SS et al. Modelling the sitagliptin effect on dipeptidyl peptidase-4 activity in adults with haematological malignancies after umbilical cord blood haematopoietic cell transplantation. Clin. Pharmacokinet. 2014; 247–59. CrossRef

53. Aljitawi OS, Paul S, Ganguly A et al. Erythropoietin modulation is associated with improved homing and engraftment after umbilical cord blood transplantation. Blood 2016; 3000–10. CrossRef

54. Guo B, Huang X, Cooper S, Broxmeyer HE. Glucocorticoid hormone promotes human hematopoietic stem cell homing and engraftment by chromatin remodeling. Nat. Med. 2017; 424-28. CrossRef

55. Shoulars K, Noldner P, Troy JD et al. Development and validation of a rapid, aldehyde dehydrogenase bright-based cord blood potency assay. Blood 2016; 2346–54. CrossRef

56. Broxmeyer HE, Pelus LM. Inhibition of DPP4/CD26 and dmPGE(2) treatment enhances engraftment of mouse bone marrow hematopoietic stem cells. Blood Cells Mol. Dis. 2014; 34–8. CrossRef

Affiliations

Hal E Broxmeyer

Department of Microbiology and Immunology,
Indiana University School of Medicine,
Indianapolis,
Indiana,
USA

This work is licensed under a Creative Commons Attribution- NonCommercial – NoDerivatives 4.0 International License.