Hoxworth

Research

Research at the Hoxworth Blood Center has been carried out since its founding in 1938, by Paul I Hoxworth MD. Tibor Greenwalt MD, who succeeded him as director, worked to transform blood banking into the field of transfusion medicine, and initiated a dedicated research division in 1979. Jose Cancelas, MD, PhD, the current director, continues to foster this momentum.

The goal of the Research Division is to link basic research with clinical care, leading to improved methods that ensure the quality, safety and efficacy of the blood and hematopoietic cell supply. The research program has multiple components, including clinical research, basic biological research, and translational research.

The division is one of the leaders in the coordination of research projects developed for the advancement of transfusion medicine, including FDA required clinical trials for licensing new transfusion medicine-related products. These projects encompass a broad range of studies. They include the evaluation of new methods for processing and storing red blood cells (RBCs), platelets, and plasma; pathogen inactivation treatment of RBCs and platelets; and the development and testing of new assays used in these evaluations.

Basic research in the division focuses on the study of blood-forming cells during the process of adult hematopoiesis (hematopoietic stem cell biology). This process results in billions of cells that are produced daily in a highly regulated fashion to provide all functional blood cell types (neutrophils, eosinophils, basophils, monocytes/macrophages, platelets, and erythrocytes) in order to maintain homeostatic cell counts, and other tissue cells (mast cells and osteoclasts). Adult hematopoiesis is located in the bone marrow and is initiated by hematopoietic stem cells (HSC). These are able to self-renew and differentiate into all types of blood cells. They are of clinical interest because of their potential use in stem cell and gene therapy.

Currently, we are developing new methods to study the basic biology and regulation of adult stem cell proliferation and differentiation. Our aim is to link these studies with bioengineering processes that might allow us to develop blood products from adult stem cells. There are two major areas of focus in our laboratories:

  1. Clinical Research in Transfusion Medicine

  2. Stem Cell Biology (Hematopoietic and Mesenchymal/Stromal)

Current Projects:

  • Pathogen inactivation of red blood cell and platelet products
  • Evaluation of lyophilized fresh frozen plasma
  •  Evaluation of lyophilized platelet products
  • Validation of a biotin labeling technique for assaying RBC survival 
  • Rac GTPases inhibition in chronic myelogenous leukemia
  • Vav / Rac as a molecular target in pediatric acute lymphoblastic leukemia
  • Connexin-43 in bone marrow failure after cancer-related chemotherapy

Compliance:

All studies are reviewed and approved by the Institutional Review Board of the University of Cincinnati Medical Center and Radiation Safety where applicable. Current Good Manufacturing Practices are followed in performance of all procedures, and the laboratory meets the standards of all sponsors as determined by on-site inspections.

Selected Publications:

The Research Divisions findings have been published in prestigious, peer-reviewed, national and international journals. A few examples published in the last 5 years can be found below:

The Research Divisions findings have been published in prestigious, peer-reviewed, national and international journals including Nature, Nature Medicine, Cell Stem Cell, Cancer Cell, PNAS, Blood, Leukemia and Transfusion.

  1. Adori C, Daraio T, Kuiper R, Barde S, Horvathova L, Yoshitake T, Ihnatko R, Valladolid-Acebes I, Vercruysse P, Wellendorf AM, Gramignoli R, Bozoky B, Kehr J, Theodorsson E, Cancelas JA, Mravec B, Jorns C, Ellis E, Mulder J, Uhlén M, Bark C, Hökfelt T. Disorganization and degeneration of liver sympathetic innervations in nonalcoholic fatty liver disease revealed by 3D imaging. Sci Adv. 2021;7(30):eabg5733. doi: 10.1126/sciadv.abg5733. PMID: 34290096
  2. Fan Y, Teng Y, Loison F, Pang A, Kasorn A, Shao X, Zhang C, Ren Q, Yu H, Zheng Y, Cancelas JA, Manis J, Chai L, Park SY, Zhao L, Xu Y, Feng S, Silberstein LE, Ma F, Luo HR. Targeting multiple cell death pathways extends the shelf life and preserves the function of human and mouse neutrophils for transfusion. Sci Transl Med. 2021;13(604):eabb1069. doi: 10.1126/scitranslmed.abb1069. PMID: 34321317 NIHMS 1734011
  3. Serrano-Lopez J, Hegde S, Kumar S, Serrano J, Fang J, Wellendorf AM, Roche PA, Rangel Y, Carrington LJ, Geiger H, Grimes HL, Luther S, Maillard I, Sanchez-Garcia J, Starczynowski DT, Cancelas JA. Inflammation rapidly recruits GMP and MDP from bone marrow into regional lymphatics. Elife 2021;10:e66190 https://doi.org/10.7554/eLife.66190 PMID: 33830019 PMC8137144
  4. Davis G, York AJ, Bacon WC, Lin SC, McNeal MM, Yarawsky AE, Maciag JJ, Miller JLC, Locker KCS, Bailey M, Stone R, Hall M, Gonzalez J, Sproles A, Woodle ES, Safier K, Justus KA, Spearman P, Ware RE, Cancelas JA, Jordan MB, Herr AB, Hildeman DA, Molkentin JD. Seroprevalence of SARS-CoV-2 infection in Cincinnati Ohio USA from August to December 2020. PLoS One 2021;16(7):e0254667. https://doi.org/10.1371/journal.pone.025466746 PMID: 34260645
  5. Singh AK, Cancelas JA. Mitochondria transfer in bone marrow hematopoietic activity. Curr Stem Cell Rep 2021 Mar;7:1-12. Epub Jan 4, 2021. https://doi.org/10.1007/s40778-020-00185-z
  6. Hegde S, Wellendorf A, Zheng Y, Cancelas JA. Antioxidant prevents clearance of hemostatically competent platelets after long-term cold storage. Transfusion. 2021;61(2):557-567. doi: 10.1111/trf.16200. PMID: 33247486. NIHMS 1681320 PMC8006927
  7. Prus K, Alquist CR, Cancelas JA, Oh D. Decrease in serum antibodies to SARS-CoV-2 in convalescent plasma donors over time. Transfusion 2021;61(2):651-4. https://doi.org/10.1111/trf.16172 PMID: 33616966 PMC8014079
  8. Golan K, Singh AK, Kollet O, Bertagna M, Althoff MJ, Khatib-Massalha E, Petrovich-Kopitman E, Wellendorf AM, Massalha H, Levin-Zaidman S, Dadosh T, Bohan B, Gawali MV, Dasgupta B, Lapidot T, Cancelas JA. Bone marrow regeneration requires mitochondrial transfer from donor Cx43-expressing hematopoietic progenitors to stroma. Blood 2020;136(23):2607-19. https://10.1182/blood.2020005399 PMID: 32929449 (Commentary: Méndez-Ferrer S. HSCs revive their niche after transplantation. Blood 2020;136(23):2597-8. https://10.1182/blood.2020008923)
  9. Nelson AS, Heyenbruch D, Rubinstein JD, Sabulski A, Jodele S, Thomas S, Lutzko C, Zhu X, Leemhuis T, Cancelas JA, Keller M, Bollard CM, Hanley PJ, Davies SM, Grimley MS. Virus-specific T-cell therapy to treat BK polyomavirus infection in bone marrow and solid organ transplant recipients. Blood Adv 2020;4(22):5745-5754. doi: 10.1182/bloodadvances.2020003073. PMID: 33216887 PMC7686882
  10. Govindarajah V, Lee J-M, Solomon M, Goddard B, Nayak N, Nattamai K, Geiger H, Salomonis N, Cancelas JA, Reynaud D. FOXO activity adaptation safeguards the hematopoietic stem cell compartment in hyperglycemia. Blood Adv 2020;4(21):5512-26. doi: 10.1182/bloodadvances.2020001826. PMID: 33166407 PMC7656925
  11. Kelly K, Cancelas JA, Szczepiorkowski ZM, Dumont DF, Rugg N, Dumont LJ. Frozen platelets - Development and future directions. Transfus Med Rev 2020;34(4):286-93. https://doi.org/10.1016/j.tmrv.2020.09.008 PMID: 33317698
  12. Althoff MJ, Nayak RC, Hegde S, Wellendorf AM, Bohan B, Filippi MD, Xin M, Lu QR, Geiger H, Zheng Y, Diaz-Meco MT, Moscat J, Cancelas JA. Yap1-Scribble polarization is required for hematopoietic stem cell division and fate. Blood 2020;136(16);1824-1836. doi: 10.1182/blood.2019004113. PMID: 32483624 PMC7568035 [Embargo to 2021/10/21]
  13. Boucher AA, Luchtman-Jones L, Palumbo JS, Cancelas JA, Abu-El-Haija M, Jenkins TM, Lin TK, Nathan JD. Extreme thrombocytosis after pediatric pancreatectomy with islet autotransplantation is unique compared to other postsplenectomy states. J Pediatr Surg. 2020;55(8):1645-50. doi: 10.1016/j.jpedsurg.2019.09.019. PMID: 31677823
  14. Rubinstein JD, Zhu X, Lutzko C, Leemhuis T, Cancelas JA, Jodele S, Bollard CM, Hanley PJ, Davies SM, Grimley MS, Nelson AS. Complement inhibition does not impair the clinical antiviral capabilities of virus-specific T-cell therapy. Blood Adv 2020;4(14):3252-3257. doi: 10.1182/bloodadvances.2020002252.PMID: 32697816 PMC7391136
  15. DʼAlessandro A, Yoshida T, Nestheide S, Nemkov T, Stocker S, Stefanoni D, Mohmoud F, Rugg N, Dunham A, Cancelas JA. Hypoxic storage of red blood cells improves metabolism and post-transfusion recovery. Transfusion. 2020;60(4):786-798. doi: 10.1111/trf.15730. PMID: 32104927 NIHMSID 1648603 PMC7899235
  16. Gasilina A, Premnauth G, Gurjar P, Biesiada J, Hegde S, Milewski D, Ma G, Kalin TV, Merino E, Meller J, Seibel W, Cancelas JA, Vinnedge LP, Nassar NN. IODVA1, a guanidinobenzimidazole derivative, targets Rac activity and Ras-driven cancer models. PLoS One. 2020;15(3):e0229801. doi: 10.1371/journal.pone.0229801. eCollection 2020. PMID: 32163428 PMC7067412
  17. Yazer MH, Spinella PC, Doyle L, Kaufman RM, Dunn R, et al, Biomedical Excellence for Safer Transfusion Collaborative. Transfusion of uncrossmatched Group O erythrocyte-containing products does not interfere with most ABO typings. Anesthesiology. 2020;132(3):525-34. doi: 10.1097/ALN.0000000000003069. PMID: 31789634
  18. Singh AK, Cancelas JA. Gap junctions in the bone marrow lympho-hematopoietic stem cell niche, leukemia progression, and chemoresistance. Int J Mol Sci. 2020 Jan 25;21(3). pii: E796. doi: 10.3390/ijms21030796. PMID: 31991829 PMC7038046
  19. Yu Y, Choi K, Wu J, Andreassen PR, Dexheimer PJ, Keddache M, Brems H, Spinner R, Cancelas JA, Martin LJ, Wallace MR, Legius E, Vogel KS, Ratner N. NF1 patient missense variants predict a role for ATM in modifying neurofibroma initiation. Acta Neuropathol 2020;139(1):157-74. doi: 10.1007/s00401-019-02086-w. PMID: 31664505 PMC7243727
  20. Atreya C, Glynn S, Busch M, Kleinman S, Snyder E, Rutter S, AuBuchon J, Flegel W, Reeve D, Devine D, Cohn C, Custer B, Goodrich R, Benjamin RJ, Razatos A, Cancelas J, Wagner S, Maclean M, Gelderman M, Cap A, Ness P. Proceedings of the Food and Drug Administration public workshop on pathogen reduction technologies for blood safety 2018. Transfusion. 2019;59(9):3002-25. doi: 10.1111/trf.15344. PMID: 31144334, PMC6726584
  21. Trump LR, Nayak RC, Singh AK, Emberesh S, Wellendorf AM, Lutzko CM, Cancelas JA. Neutrophils derived from genetically modified human induced pluripotent stem cells circulate and phagocytose bacteria in vivo. Stem Cells Transl Med 2019;8(6):557-67. https//doi.org/10.1002/sctm.18-0255. PMID: 30793529 PMC6525559
  22. Nayak RC, Hegde, S, Althoff MJ, Wellendorf AM, Mohmoud F, Perentesis J, Reina-Campos M, Reynaud D, Zheng Y, Diaz-Meco MT, Moscat J, Cancelas JA. The signaling axis atypical protein kinase C λ/ι-Satb2 mediates leukemic transformation of B-cell progenitors. Nat Commun 2019;10(1): 46. doi: 10.1038/s41467-018-07846-y, https://rdcu.be/bfqUI, PMID: 30610188. PMC6320370
  23. Zhang C, D'Alessandro A, Wellendorf AM, Mohmoud F, Serrano-Lopez J, Perentesis J, Komurov K, Alexe G, Stegmaier K, Whitsett J, Grimes HL, Cancelas JA. KLF5 controls glutathione metabolism to suppress p190-BCR-ABL+ B-cell lymphoblastic leukemia. Oncotarget Jul 3, 2018;9(51)29665-79. PMID: 30038712, PMC6049869
  24. Mock DM, Nalbant D, Kyosseva SV, Schmidt RL, An G, Matthews NI, Vlaar APJ, van Bruggen R, de Korte D, Strauss RG, Cancelas JA, Franco RS, Veng-Pedersen P, Widness JA. Development, validation, and potential applications of biotinylated red blood cells for posttransfusion kinetics and other physiological studies: evidenced-based analysis and recommendations. Transfusion Aug 2018;58(8):2068-81. Review. PMID 29770455
  25. Roy S, Rai P, Eiymo Mwa Mpollo MS, Chang KH, Rizvi T, Shanmukhappa SK, VandenHeuvel K, Aronow B, Inagami T, Cancelas JA, Malik P. Angiotensin receptor signaling in sickle cell anemia has a reno-protective effect on urine concentrating ability but results in sickle glomerulopathy. Am J Hematol Jul 2018;93(7):E177-E181. (Letter) PMID 29675906, NIHMS961332, PMC6037553
  26. Fang J, Muto T, Kleppe M, Bolanos LC, Hueneman KM, Walker CS, Sampson L, Wellendorf AM, Chetal K, Choi K, Salomonis N, Choi Y, Zheng Y, Cancelas JA, Levine RL, Starczynowski DT. TRAF6 mediates basal activation of NF-κB necessary for hematopoietic stem cell homeostasis. Cell Rep 2018 Jan 30;22(5):1250-62. PMID 29386112, NIHMS966903, PMC5971064
  27. Serrano-Lopez J, Nattamai K, Pease NA, Shephard MS, Wellendorf AM, Sertorio M, Smith EA, Geiger H, Wells SI, Cancelas JA, Privette Vinnedge LM. Loss of DEK induces radioresistance of murine restricted hematopoietic progenitors. Exp Hematol 2018 Mar;59:40-50.e3. PMID 29288703, PMC5844846
  28. Lee JM, Govindarajah V, Goddard B, Hinge A, Muench DE, Filippi MD, Aronow B, Cancelas JA, Salomonis N, Grimes HL, Reynaud D. Obesity alters the long-term fitness of the hematopoietic stem cell compartment through modulation of Gfi1 expression. J Exp Med 2018 Feb 5;215(2):627-44. PMID 29282250, PMC5789409

For more information, please contact:

Clinical studies: Neeta Rugg  at (513) 558-1525.

Basic research: Jose Cancelas at (513) 558-1324

For additional information about related research projects, select the following links.

Division of Experimental Hematology & Cell Biology of Cincinnati Children’s Hospital Medical Center.