Direct reprogramming of fibroblasts into antigen-presenting dendritic cells

Rosa, Fábio F.; Pires, Cristiana F.; Kurochkin, Ilia; Ferreira, Alexandra G.; Gomes, Andreia; Palma, Luis Galán; Shaiv, Kritika; Solanas, Laura; Azenha, Cláudia de Jesus; Papatsenko, Dmitri; Schulz, Oliver; Sousa, Caetano Reis e; Pereira, Carlos Filipe

doi:10.1126/sciimmunol.aau4292

Cited by 87 publications

(80 citation statements)

References 55 publications

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“…Such fibroblasts are reminiscent of fibrocytes, which express hematopoietic markers such as CD45, CD34, and MHCII (major histocompatibility complex class II) . Fibroblasts can be reprogrammed into induced dendritic cells (iDCs) capable of cross‐presenting antigen to CD8 + T cells . Interestingly, the immune checkpoint ligand PD‐L1/CD274 was recently reported on fibroblasts in lung fibrosis, and this possibly plays a role in fibroblast invasion and progression of idiopathic pulmonary fibrosis .…”

Section: Evolution Of the Immune Regulatory Functions Of Fibroblastsmentioning

confidence: 99%

Origin and functional heterogeneity of fibroblasts

2020

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The inherent plasticity and resiliency of fibroblasts make this cell type a conventional tool for basic research. But where do they come from, are all fibroblasts the same, and how do they function in disease? The first fibroblast lineages in mammalian development emerge from the ooze of primary mesenchyme during gastrulation. They are cells that efficiently create and negotiate the extracellular matrix of the mesoderm in order to migrate and meet their developmental fate. Mature fibroblasts in epithelial tissues live in the interstitial spaces between basement membranes that spatially delimit complex organ structures. While the function of resident fibroblasts in healthy tissues is largely conjecture, the accumulation of fibroblasts in pathologic lesions offers insight into biologic mechanisms that control their function; fibroblasts are poised to coordinate fibrogenesis in tissue injury, neoplasia, and aging. Here, we examine the developmental origin and plasticity of fibroblasts, their molecular and functional definitions, the epigenetic control underlying their identity and activation, and the evolution of their immune regulatory functions. These topics are reviewed through the lens of fate mapping using genetically engineered mouse models and from the perspective of single‐cell RNA sequencing. Recent observations suggest dynamic and heterogeneous functions for fibroblasts that underscore their complex molecular signatures and utility in injured tissues.

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Section: Evolution Of the Immune Regulatory Functions Of Fibroblastsmentioning

confidence: 99%

Origin and functional heterogeneity of fibroblasts

2020

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“…The specific expression pattern of Clec9a, particularly in humans, can also be used as a specific signature to track cDC1s ( Table 1). For instance, the Clec9a promoter has been used as a reporter system for the reprogramming of fibroblasts into the cDC1 lineage with the transcription factors PU.1, IRF8, and BATF3 (34). This is of relevance in cancer immunology, where cDC1 infiltration within solid tumors has been associated with effective antitumor immunity and prognosis of increased overall survival in a variety of tumor types (35)(36)(37).…”

Section: Dngr-1 As a Targetable Cdc1 Markermentioning

confidence: 99%

DNGR-1, a Dendritic Cell-Specific Sensor of Tissue Damage That Dually Modulates Immunity and Inflammation

2020

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DNGR-1 (encoded by CLEC9A) is a C-type lectin receptor (CLR) with an expression profile that is mainly restricted to type 1 conventional dendritic cells (cDC1s) both in mice and humans. This delimited expression pattern makes it appropriate for defining a cDC1 signature and for therapeutic targeting of this population, promoting immunity in mouse models. Functionally, DNGR-1 binds F-actin, which is confined within the intracellular space in healthy cells, but is exposed when plasma membrane integrity is compromised, as happens in necrosis. Upon F-actin binding, DNGR-1 signals through SYK and mediates cross-presentation of dead cell-associated antigens. Cross-presentation to CD8 + T cells promoted by DNGR-1 during viral infections is key for cross-priming tissue-resident memory precursors in the lymph node. However, in contrast to other closely related CLRs such as Dectin-1, DNGR-1 does not activate NFκB. Instead, recent findings show that DNGR-1 can activate SHP-1 to limit inflammation triggered by heterologous receptors, which results in reduced production of inflammatory chemokines and neutrophil recruitment into damaged tissues in both sterile and infectious processes. Hence, DNGR-1 reduces immunopathology associated with tissue damage, promoting disease tolerance to safeguard tissue integrity. How DNGR-1 signals are conditioned by the microenvironment and the detailed molecular mechanisms underlying DNGR-1 function have not been elucidated. Here, we review the expression pattern and structural features of DNGR-1, and the biological relevance of the detection of tissue damage through this CLR.

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“…However, generation of mature hematopoietic cells with the ability to modulate immune responses remains largely unexplored. Recently, our group provided evidence that antigen-presenting DCs can be induced from mouse and human fibroblasts by a combination of three instructive transcription factors (147). In the next sections, we will dwell on our strategy to identify such factors, how this approach informs development and lineage heterogeneity, as well as how it can be expanded to other immune cell types and lead to the development of powerful immunotherapies.…”

Section: Instructorsmentioning

confidence: 99%

“…We hypothesized that lineage reprogramming could be employed to generate antigen-presenting DCs from mouse and human fibroblasts ( Figure 3A) (147). In order to identify instructive factors to impose DC fate, we first compiled a list of 18 candidate factors whose expression is restricted to the DC lineage and enriched during DC ontogeny.…”

Section: Reprogramming Antigen-presenting Dendritic Cellsmentioning

confidence: 99%

Understanding and Modulating Immunity With Cell Reprogramming

et al. 2019

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Cell reprogramming concepts have been classically developed in the fields of developmental and stem cell biology and are currently being explored for regenerative medicine, given its potential to generate desired cell types for replacement therapy. Cell fate can be experimentally reversed or modified by enforced expression of lineage specific transcription factors leading to pluripotency or attainment of another somatic cell type identity. The possibility to reprogram fibroblasts into induced dendritic cells (DC) competent for antigen presentation creates a paradigm shift for understanding and modulating the immune system with direct cell reprogramming. PU.1, IRF8, and BATF3 were identified as sufficient and necessary to impose DC fate in unrelated cell types, taking advantage of Clec9a, a C-type lectin receptor with restricted expression in conventional DC type 1. The identification of such minimal gene regulatory networks helps to elucidate the molecular mechanisms governing development and lineage heterogeneity along the hematopoietic hierarchy. Furthermore, the generation of patient-tailored reprogrammed immune cells provides new and exciting tools for the expanding field of cancer immunotherapy. Here, we summarize cell reprogramming concepts and experimental approaches, review current knowledge at the intersection of cell reprogramming with hematopoiesis, and propose how cell fate engineering can be merged to immunology, opening new opportunities to understand the immune system in health and disease.

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Direct reprogramming of fibroblasts into antigen-presenting dendritic cells

Cited by 87 publications

References 55 publications

Origin and functional heterogeneity of fibroblasts

Origin and functional heterogeneity of fibroblasts

DNGR-1, a Dendritic Cell-Specific Sensor of Tissue Damage That Dually Modulates Immunity and Inflammation

Understanding and Modulating Immunity With Cell Reprogramming

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