Luisa Natalia Pimentel Vera

All Publications

• CNS-wide repopulation by hematopoietic-derived microglia-like cells corrects progranulin deficiency in mice. Nature communications Colella, P., Sayana, R., Suarez-Nieto, M. V., Sarno, J., Nyame, K., Xiong, J., Pimentel Vera, L. N., Arozqueta Basurto, J., Corbo, M., Limaye, A., Davis, K. L., Abu-Remaileh, M., Gomez-Ospina, N. 2024; 15 (1): 5654

  Abstract

  Hematopoietic stem cell transplantation can deliver therapeutic proteins to the central nervous system (CNS) through transplant-derived microglia-like cells. However, current conditioning approaches result in low and slow engraftment of transplanted cells in the CNS. Here we optimized a brain conditioning regimen that leads to rapid, robust, and persistent microglia replacement without adverse effects on neurobehavior or hematopoiesis. This regimen combines busulfan myeloablation and six days of Colony-stimulating factor 1 receptor inhibitor PLX3397. Single-cell analyses revealed unappreciated heterogeneity of microglia-like cells with most cells expressing genes characteristic of homeostatic microglia, brain-border-associated macrophages, and unique markers. Cytokine analysis in the CNS showed transient inductions of myeloproliferative and chemoattractant cytokines that help repopulate the microglia niche. Bone marrow transplant of progranulin-deficient mice conditioned with busulfan and PLX3397 restored progranulin in the brain and eyes and normalized brain lipofuscin storage, proteostasis, and lipid metabolism. This study advances our understanding of CNS repopulation by hematopoietic-derived cells and demonstrates its therapeutic potential for treating progranulin-dependent neurodegeneration.

  View details for DOI 10.1038/s41467-024-49908-4

  View details for PubMedID 38969669

  View details for PubMedCentralID PMC11226701

• Improved engraftment and therapeutic efficacy by human genome-edited hematopoietic stem cells with Busulfan-based myeloablation. Molecular therapy. Methods & clinical development Poletto, E., Colella, P., Pimentel Vera, L. N., Khan, S., Tomatsu, S., Baldo, G., Gomez-Ospina, N. 2022; 25: 392-409

  Abstract

  Autologous hematopoietic stem cell transplantation using genome-edited cells can become a definitive therapy for hematological and non-hematological disorders with neurological involvement. Proof-of-concept studies using human genome-edited hematopoietic stem cells have been hindered by the low efficiency of engraftment of the edited cells in the bone marrow and their modest efficacy in the CNS. To address these challenges, we tested a myeloablative conditioning regimen based on Busulfan in an immunocompromised model of mucopolysaccharidosis type 1. Compared with sub-lethal irradiation, Busulfan conditioning enhanced the engraftment of edited CD34+ cells in the bone marrow, as well the long-term homing and survival of bone-marrow-derived cells in viscera, and in the CNS, resulting in higher transgene expression and biochemical correction in these organs. Edited cell selection using a clinically compatible marker resulted in a population withlow engraftment potential. We conclude that conditioning can impact the engraftment of edited hematopoietic stem cells.Furthermore, Busulfan-conditioned recipients have a higher expression of therapeutic proteins in target organs, particularly in the CNS, constituting a better conditioning approach for non-hematological diseases with neurological involvement.

  View details for DOI 10.1016/j.omtm.2022.04.009

  View details for PubMedID 35573043