Giorgetti Group

Hematopoietic Stem Cell Biology and Leukemogenesis

Identification of Molecular and Cellular Pathways involved in hematopoietic stem cell specification and oncogenic transformation

Hematopoiesis is a hierarchical process controlled by a rare population of multipotent hematopoietic stem cells (HSCs). Inherited disorders affecting HSCs and their progeny are responsible for malignant and non-malignant hematological diseases. The goal of studying hematopoietic development is not only to elucidate the development trajectory of blood cells, but also to provide insights for treatment of hematological disorders.
Alessandra Giorgetti
Principal Investigator, Regenerative Medicine Program of IDIBELL
Associate Professor, Department of Pathology and Experimental Therapy, University of Barcelona
Associated Group Leader of P-CMRC

Lab Focus-Elucidating molecular and cellular mechanism regulating hematopoietic development

Hematopoietic stem cells (HSCs) are considered the base of adult hematopoiesis. Currently, most of these hematological disorders are curable by HSC transplantation. However, the limited availability of optimally human matched donor remains a challenge, especially for individuals of non-Caucasian background or mixed ethnicity. Human pluripotent stem cells (PSCs), including embryonic stem cells (hESCs) and induced PSCs (hiPSCs), can differentiate in vitro into various hematopoietic cell type and could represent an ideal source of customized HSCs for clinical application. Furthermore, HSCs derived from patient-iPSCs not only represent an invaluable hematological disease modeling but might provide a cell-based platform for therapeutic screening. The production of engrafting HSCs from human PSCs will depend on the accurate recapitulation of embryonic hematopoiesis. Currently, our laboratory is working on 1) identification of developmental pathways involved in the generation of HSCs to direct the differentiation of PSCs into clinically relevant hematopoietic cells; 2) developing iPS cell based models of blood cancer stem cell development. These goals will be realized by combining genomics, transcriptomics, gene editing and cell biological techniques.

Why it matters

Understanding the hematopoietic development it is crucial to faithfully reproduce the process of HSC development in vitro generating cell replacement therapies for the treatment of blood-related genetic diseases and leukaemia.

Keywords

Hematopoietic Stem Cell (HSC), blood cancer, reprogramming, induced pluripotent stem cells (iPSCs)

Publications

Fernández-Muñoz B, Rosell-Valle C, Ferrari D, Alba-Amador J, Montiel MÁ, Campos-Cuerva R, Lopez-Navas L, Muñoz-Escalona M, Martín-López M, Profico DC, Blanco MF, Giorgetti A, González-Muñoz E, Márquez-Rivas J, Sanchez-Pernaute R. Retrieval of germinal zone neural stem cells from the cerebrospinal fluid of premature infants with intraventricular hemorrhage. Stem Cells Transl Med. (2020). Online ahead of print.

Castaño J, Aranda S, Bueno C, Calero-Nieto FJ, Mejia-Ramirez E, Blanco E, Wang X, Prieto C, Zabaleta L, Rovira M, Jiménez-Delgado S, Gӧttgens B, Di Croce L, Menendez P, Raya A and Giorgetti A. GATA2 directly represses cardiac fates to promote hematopoietic specification of human mesoderm. Stem Cell Reports, 13:515-529. (2019).
Giorgetti A*; Castaño J; Bueno C; Diaz GR; Delgado M, Espinosa L; Menendez P*. Proinflammatory signals are insufficient to drive definitive hematopoietic specification of human HSCs in vitro. Exp Hematol. 45; 85-93. (2017). *co-corresponding authors
Muñoz-López A, Romero-Moya D, Prieto D, Ramos-Mejía V, Agraz-Doblas A, Varella I, Buschbeck M, Palau A, Carvajal-Vergara A, Giorgetti A, Ford A, Lako M, Granada I, Ruiz-Xivillé, Rodríguez-Perales S, Stam RW, Fraga MF, Nakanishi M, Cazzaniga G, Bardini M, Fernandez AF, Bueno C, Menendez P. Developmental refractoriness of MLL-rearranged human B-cell acute leukemias to reprogramming into pluripotency. (2016). Stem Cell Reports;7:602-618. (2016).
Castaño, J; Menéndez, P; Bruzos, C; Straccia, M; Sousa, M; Zabaleta, L; Vázquez, N; Zubiarrain, A; Canals, JM; Sonntag, KC; Ugedo, L; Carvajal-Vergara, X; Torrecilla, M; Sánchez-Pernaute, R; Giorgetti, A. Rapid and efficient direct conversion of human hematopoietic cells into neurons by SOX2 and c-MYC Sendai vectors. Stem Cell Reports. 3:1118-1131. (2014).
Ruiz S, Gore A, Li Z, Panopoulos AD, Montserrat N, Fung HL, Giorgetti A, Bilic J, Batchelder EM, Zaehres H, Schöler HR, Zhang K, Izpisua Belmonte JC. Analysis of protein-coding mutations in hiPSCs and their possible role during somatic cell reprogramming. Nat Commun. 4, 1382. (2013).
Giorgetti A, Marchetto MC, Li M, Yu D, Fazzina R, Mu Y, Adamo A, Paramonov I, Castaño J, Monasterio MB, Bardy C, Cassiani-Ingoni R, Liu GH, Gage FH, Izpisúa Belmonte JC.. Cord blood-derived neuronal cells by ectopic expression of SOX2 and c-MYC. Proc Natl Acad Sci U S A. 109, 12556-61. (2012)
Gore A, Li Z, Fung HL, Young JE, Agarwal S, Antosiewicz-Bourget J, Canto I, Giorgetti A, Israel MA, Kiskinis E, Lee JH, Loh YH, Manos PD, Montserrat N, Panopoulos AD, Ruiz S, Wilbert ML, Yu J, Kirkness EF, Izpisúa Belmonte JC, Rossi DJ, Thomson JA, Eggan K, Daley GQ, Goldstein LS, Zhang K. Somatic coding mutations in human induced pluripotent stem cells. Nature. 471, 63-7 (2011).
Giorgetti A, Montserrat N, Rodriguez-Piza I, Azqueta C, Veiga A and Izpisúa Belmonte JC. Generation of induced pluripotent stem cells from human cord blood with only two factors: Oct4 and Sox2. Nature Protocols. 5, 811-820 (2010)
Giorgetti A, Montserrat N, Aasen T, Gonzalez F, Rodríguez-Pizà I, Vassena R, Raya A, Boué S, Barrero MJ, Aran-Corbella B, Torrabadella M, Veiga A and Izpisúa Belmonte JC.. Generation of induced pluripotent stem cells from human cord blood using OCT4 and SOX2. Cell Stem Cell. 5, 353-358. (2009)
Current Members
Current Members
Damià Romero
Research Assistant

Alessandra Giorgetti
Principal Investigator, Regenerative Medicine Program of IDIBELL
Associate Professor, Department of Pathology and Experimental Therapy, University of Barcelona
Associated Group Leader of P-CMRC
agiorgetti@idibell.cat

Alessandra Giorgetti holds a PhD in Molecular Medicine (2004) from the University of Milan, (Italy). She continued her Postdoc training in Dr. Rafii’s Laboratory, at Weill Cornell Medical College in New York. She then was a Research Associate (2008-2011) at the Center of Regenerative Medicine of Barcelona (CMRB). There, she consolidated her skills in stem cells and acquired invaluable knowledge in reprogramming technologies. From 2011 to 2013 she was the head of the Laboratory of Hematopoiesis and Blood Disorders at the Inbiomed Foundation, San Sebastian (Spain). In 2014 she was awarded with the prestigious Spanish grant Ramon y Cajal, in the area of Biomedicine. The same year she joined Pablo Menendez’ Lab, at the Josep Carreras Leukaemia Research Institute, as associate Investigator.

Since 2016 she is employed at the CMRB, where she established her own research group studying the molecular mechanisms that regulate human hematopoietic stem cell development, differentiation and oncogenic transformation. GATA2 deficiency disorder became a more recent focus of her group. Employing multi-OMICs methodologies (genome, transcriptome and epigenome), human induced pluripotent stem cells (hiPSCs) and in vivo experimental models she is interested to understand how GATA2 haploinsufficiency contributes to myelodysplastic syndrome /acute myeloid leukemia development in pediatric patients.

Damià Romero
Research Assistant
dromero@idibell.cat

Damià Romero holds a BS in Biology (2010), an MS in Biomedicine (2011), and a PhD in Biomedicine (2017) obtained at the University of Barcelona (UB)

During his PhD at Josep Carreras Leukemia Research Institute in Barcelona (IJC-UB) (Prof. Pablo Menendez) he developed an iPSC model to recapitulate the Coenzyme Q10 deficiency to understand the genotype-phenotype association. He used isogenic iPSCs to study differences on the metabolism and cell differentiation. He also studied the contribution of mitochondria in cord blood-derived hematopoietic stem cells. During this period, he performed a short stay of 4 month at Institute of Genetics Medicine (IGM) at the University of Newcastle in the laboratory of Prof. Majlinda Lako to better understand the biology of the iPSCs.

He spent three years as a postdoc in Dr. Jeroen Roose´s lab at University of California San Francisco (UCSF) developing a mouse model with the expression of human RasGRP1 resulting in impaired blood differentiation. This study was combined with a synthetic lethal screening to discover new targets to treat T-ALL.

During these years he has acquired expertise in cell culture techniques (including stem cells, hES, hiPSC), molecular biology, immunology, gen editing, mice model handling and deep knowledge of hematopoiesis and leukemia.

In 2020, he joined P-CMRC in Giorgetti’s Lab as Research Assistant.