Ami Patel1, Cara Marie Clementelli1, Danuta Jarocha2, Gohar Mosoyan3, Cindy Else4, Manisha Kintali1, Helen Fong5, Jay Tong6, Ronald Gordon7, Virginia Gillespie4, Alla Keyzner1, Mortimer Poncz8, Ronald Hoffman1, Camelia Iancu-Rubin1,7. 1. Division of Hematology and Medical Oncology, Tisch Cancer Institute and the Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York. 2. Division of Hematology, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania. 3. Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York. 4. Comparative Pathology Laboratory in the Center for Comparative Medicine and Surgery, Icahn School of Medicine at Mount Sinai, New York, New York. 5. Sangamo Therapeutics, Inc., Richmond, California. 6. AllCells, LLC, Alameda, California. 7. Department of Pathology, Molecular and Cell-Based Medicine, Icahn School of Medicine at Mount Sinai, New York, New York. 8. Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania.
Abstract
BACKGROUND: Platelet (PLT) transfusions are the most effective treatments for patients with thrombocytopenia. The growing demand for PLT transfusion products is compounded by a limited supply due to dependency on volunteer donors, a short shelf-life, risk of contaminating pathogens, and alloimmunization. This study provides preclinical evidence that a third-party, cryopreservable source of PLT-generating cells has the potential to complement presently available PLT transfusion products. STUDY DESIGN AND METHODS: CD34+ hematopoietic stem/progenitor cells derived from umbilical cord blood (UCB) units were used in a simple and efficient culture system to generate a cell product consisting of megakaryocytes (MKs) at different stages of development. The cultures thus generated were evaluated ex vivo and in vivo before and after cryopreservation. RESULTS: We generated a megakaryocytic cell product that can be cryopreserved without altering its phenotypical and functional capabilities. The infusion of such a product, either fresh or cryopreserved, into immune-deficient mice led to production of functional human PLTs which were observed within a week after infusion and persisted for 8 weeks, orders of magnitude longer than that observed after the infusion of traditional PLT transfusion products. The sustained human PLT engraftment was accompanied by a robust presence of human cells in the bone marrow (BM), spleen, and lungs of recipient mice. CONCLUSION: This is a proof-of-principle study demonstrating the creation of a cryopreservable megakaryocytic cell product which releases functional PLTs in vivo. Clinical development of such a product is currently being pursued for the treatment of thrombocytopenia in patients with hematological malignancies.
BACKGROUND: Platelet (PLT) transfusions are the most effective treatments for patients with thrombocytopenia. The growing demand for PLT transfusion products is compounded by a limited supply due to dependency on volunteer donors, a short shelf-life, risk of contaminating pathogens, and alloimmunization. This study provides preclinical evidence that a third-party, cryopreservable source of PLT-generating cells has the potential to complement presently available PLT transfusion products. STUDY DESIGN AND METHODS: CD34+ hematopoietic stem/progenitor cells derived from umbilical cord blood (UCB) units were used in a simple and efficient culture system to generate a cell product consisting of megakaryocytes (MKs) at different stages of development. The cultures thus generated were evaluated ex vivo and in vivo before and after cryopreservation. RESULTS: We generated a megakaryocytic cell product that can be cryopreserved without altering its phenotypical and functional capabilities. The infusion of such a product, either fresh or cryopreserved, into immune-deficient mice led to production of functional human PLTs which were observed within a week after infusion and persisted for 8 weeks, orders of magnitude longer than that observed after the infusion of traditional PLT transfusion products. The sustained human PLT engraftment was accompanied by a robust presence of human cells in the bone marrow (BM), spleen, and lungs of recipient mice. CONCLUSION: This is a proof-of-principle study demonstrating the creation of a cryopreservable megakaryocytic cell product which releases functional PLTs in vivo. Clinical development of such a product is currently being pursued for the treatment of thrombocytopenia in patients with hematological malignancies.
Authors: Kamaleldin E Elagib; Ashton Brock; Cara M Clementelli; Goar Mosoyan; Lorrie L Delehanty; Ranjit K Sahu; Alexandra Pacheco-Benichou; Corinne Fruit; Thierry Besson; Stephan W Morris; Koji Eto; Chintan Jobaliya; Deborah L French; Paul Gadue; Sandeep Singh; Xinrui Shi; Fujun Qin; Robert Cornelison; Hui Li; Camelia Iancu-Rubin; Adam N Goldfarb Journal: J Clin Invest Date: 2022-10-03 Impact factor: 19.456
Authors: Denys Pogozhykh; Dorothee Eicke; Oleksandr Gryshkov; Willem F Wolkers; Kai Schulze; Carlos A Guzmán; Rainer Blasczyk; Constança Figueiredo Journal: Int J Mol Sci Date: 2020-10-16 Impact factor: 5.923