Research

Merging Stem Cells with Immunology by Cell Fate Reprogramming. Learn more about our research lines:

Modeling Hematopoietic Stem Cell Generation with Cell Reprogramming

Hematopoietic Stem Cell (HSC) transplantation whether from bone marrow, mobilized peripheral blood or cord blood is the best example of regenerative cell therapy. HSCs have remarkable therapeutic applications in a broad range of diseases that affect the blood forming and immune system. Nevertheless, there remains a shortage of usable genetically-matched material for all needs. We employ an innovative approach to investigate the establishment of HSC identity: we screen for factors that re-create this unique cell state from fibroblasts. This approach leads to the identification of master transcription factors, cell surface phenotypes and gene expression signatures of induced cell fate. We then ask whether a similar logic applies to the specification of HSCs during mouse and human embryogenesis and use this information to uncover general principles of blood cell specification. We have demonstrated the direct reprogramming of mouse and human fibroblasts into clonogenic hematopoietic progenitors with the combination of transcription factors GATA2, GFI1B and FOS. We further established that cellular reprogramming approaches can inform the developmental specification of hematopoietic stem cells and shown that cooperative transcription factor binding mediates human hemogenic induction.

Working on this project

Camila Vazquez Echegaray, PhD

Marie Curie Postdoctoral Fellow

Ilia Kurochkin, PhD

CRI Computational Postdoctoral Fellow

Related to this project

GATA2 Mitotic Bookmarking Is Required for Definitive Haematopoiesis

Rita Silvério-Alves, Ilia Kurochkin, Anna Rydström, Camila Vazquez Echegaray, Jakob Haider, Matthew Nicholls, Christina Rode, Louise Thelaus, Aida Yifter Lindgren, Alexandra Gabriela Ferreira, Rafael Brandão, Jonas Larsson, Marella de Bruijn, Javier Martin-Gonzalez, Carlos-Filipe Pereira

Aug 14th, 2023 / 14:4645
Nature Communications

Mechanism for turning skin cells into blood stem cells uncovered

Human skin cells have been converted successfully into blood stem cells at the Pereira Lab, bringing new therapies for people with blood diseases a step closer. This international project – including scientist from Sweden, USA, Russia, and Portugal – follows our previous research on the reprogramming of mouse skin cells into blood stem cells. In this study we shift our focus from the specification of mouse to human hematopoietic stem cells. We describe the generation of hemogenic precursors from human fibroblasts via an endothelial intermediate and highlight the general importance of transcription factor cooperation during human hematopoietic stem cell specification.

Understanding Immune Cell Diversity with Direct Cell Reprogramming

Cellular reprogramming rewires the transcriptional and epigenetic network of one cell state to that of a different cell type. Somatic cells can be reprogrammed into induced pluripotent stem cells by the expression of transcription factor (TF) combinations. Alternative somatic cell fates can also be instructed by direct reprogramming using TFs specifying target-cell identity as demonstrated for myocytes, neurons, cardiomyocytes, among others. In hematopoiesis, progenitors and mature cells have also been generated employing this strategy. Nevertheless, reprogramming approaches have been mainly restricted to regenerative medicine and there is momentum to bring these concepts to immunology. Hence, we have shown for the first time that dendritic cell identity an antigen presentation can be programmed by a small combination of transcription factors – PU.1, IRF8 and BATF3 – providing evidence that immune cells and triggered immune responses can be modulated through cell reprogramming. We now extend our reprogramming studies to the specification of immune cell-types with therapeutic interest and broader types of reprogramming. The minimal networks identified by direct induction of immune cell-types will be instrumental to elucidate the establishment of different cell identities and the exclusion of alternative cell fates throughout immune cell development.

Working on this project

Abigail Altman

PhD Student

Ilia Kurochkin, PhD

CRI Computational Postdoctoral Fellow

Inês Caiado

PhD Student

Luís Henriques-Oliveira

PhD Student

Nejc Arh

PhD Student

Related to this project

Single-Cell Transcriptional Profiling Informs Efficient Reprogramming of Human Somatic Cells to Cross-Presenting Dendritic Cells

Fábio F. Rosa, Cristiana F. Pires, Ilia Kurochkin, Evelyn Halitzki, Tasnim Zahan, Nejc Arh, Olga Zimmermannová, Alexandra G. Ferreira, Hongzhe Li, Stefan Karlsson, Stefan Scheding, Carlos-Filipe Pereira

Mar 4th, 2022 / Vol. 7, No. 69
Science Immunology

A code for reprogramming immune sentinels

For the first time, the Pereira Lab has successfully reprogrammed mouse and human skin cells into immune cells called dendritic cells. The process is quick and effective, representing a pioneering contribution for applying direct reprogramming for inducing immunity. Importantly, this finding opens up the possibility of developing novel dendritic cell-based immunotherapies against cancer.

Harnessing Dendritic Cell Reprogramming for Cancer Immunotherapy

An important hallmark of cancer is the ability to evade the immune system. Genetic mutations in tumor cells result in the accumulation of tumor antigens, however, increased cell heterogeneity, downregulation of antigen presentation or inhibition of immune cell infiltration allows immune surveillance evasion. For the first time, direct cell reprogramming offers exciting opportunities to overcome these challenges. The Pereira Lab has recently identified a combination of transcription factors sufficient to reprogram mouse fibroblasts into antigen-presenting dendritic cells, providing a new strategy to set in motion antigen-specific immune responses. We are working on the hypothesis that a similar combination reprograms tumor cells into antigen presenting cells. This research line aims to test a cancer immunotherapy concept based on dendritic cell reprogramming and endowed antigen presenting function in tumor cells. With this approach we aim to combine DCs’ antigen processing and presenting abilities with the endogenous generation of tumor antigens. The induction of DC identity in cancer cells with ability to present a constellation of tumor antigens will open new research and therapeutic avenues. In this line we aim to merge cell reprogramming and cancer immunotherapy, paving the way for entirely new approaches to cancer therapy.

Working on this project

Ervin Aščić

PhD Student

Ilia Kurochkin, PhD

CRI Computational Postdoctoral Fellow

Olga Zimmermannova, MD PhD

Cancerfonden Postdoctoral Fellow

Related to this project

Restoring Tumor Immunogenicity with Dendritic Cell Reprogramming

Olga Zimmermannova, Alexandra G. Ferreira, Ervin Ascic, Marta Velasco Santiago, Ilia Kurochkin, Morten Hansen, Özcan Met, Inês Caiado, Ilja E. Shapiro, Justine Michaux, Marion Humbert, Diego Soto-Cabrera, Hreinn Benonisson, Rita Silvério-Alves, David Gomez-Jimenez, Carina Bernardo, Monika Bauden, Roland Andersson, Mattias Höglund, Kenichi Miharada, Yukio Nakamura, Stephanie Hugues, Lennart Greiff, Malin Lindstedt, Fábio F. Rosa, Cristiana F. Pires, Michal Bassani-Sternberg, Inge Marie Svane, Carlos-Filipe Pereira

Jul 7th, 2023 / Vol. 8, Issue 85
Science Immunology

Prestigious ERC consolidator grant for innovative immunotherapy research at the Pereira Lab

Filipe Pereira was today announced as one of the 89 selected researchers by the European Research Council of its latest Consolidator Grant competition. He will be awarded an ERC Consolidator Grant of 2 million EUR over a period of five years. The project will merge the cell reprogramming and cancer immunotherapy fields to develop innovative therapeutic strategies.