The Stem Cell and Development (SCD) research group investigates the differentiation of human pluripotent stem cells to mature and functional cardiomyocytes or dopaminergic neurons to treat disease. The SCD studies the regulation of cellular coordination (timing) and the regulation of gene expression, each essential for cellular homeostasis and typically aberrant in disease.
The goal of the SCD group is to develop robust and reproducible methodologies allowing the production of large quantities of homogeneous populations of both cardiomyocytes and dopaminergic neurons. This will be conducted alongside the characterization of coordinated transcription timing during development, essential for cell homeostasis.
The SCD group is composed of 6 research groups with complementary expertise, that investigate the complete process of cellular differentiation from pluripotency to terminal differentiation and the temporal coordination and regulation of transcription.
José Bragança (Coordinator, Principal Investigator)
Gustavo Tiscornia (Principal Investigator)
Inês Araújo (Principal Investigator)
Isabel Palmeirim (Principal Investigator)
Rui Martinho (Principal Investigator)
Leonor Faleiro (Principal Investigator)
Raquel P. Andrade (Principal Investigator)
Clévio Nóbrega (Principal Investigator)
Ana Marreiros (Phd Student)
Ana Cristina Fernandes (MsC Student)
Inês Rodrigues (PhD Student)
Isabel Duarte (Fellowship)
Rita Bastos (MsC Student)
Patrícia Gomes (PhD Student)
Jessie Bosisio de Melo
Ana Luisa Ribeiro
Ana Maria Mesquita
SDC Associated Laboratories
SCD Objectives ________________________________________________________________
Pathways and regulatory mechanisms in the maintenance of the pluripotent state and early differentiation to ectodermal and mesodermal lineages
The SCDB is developing new molecular insights in the maintenance of ESC pluripotency, as well as their early commitment into ectodermal and mesodermal lineages. The SCDB will apply these novel model systems to divulge early mechanisms involved in normal heart development and where aberrant, present congenital heart defects. The SCDB will model congenital heart defects by reprogramming iPSc from patients. The SCDB will continue to develop reliable and efficient methods to obtain cardiac progenitor and neuronal progenitor cells from our ESC/iPSc. This will greatly benefit and complement the Molecular and Regenerative Medicine Laboratory in iPSc reprogramming, and from the Neurogenesis Lab knowledge regarding neuron biology.
Investigate the bacterial switch from environmental mode of life to inside human cells
The majority of studies done on the ability of bacterial pathogens to change from a saprophyte mode of life to within human cells rely on laboratory strains behaviour that differ significantly (in regard to protein expression) from their wild counterparts. The SCDB unit will investigate this further using wild isolates to examine how they sense and respond the complex gastrointestinal milieu. The development of this subject will allow the continued identification of new factors that support bacteria to switch from life in the environment to within human cells. Having in consideration that autoimmune patients are more susceptible to infections and show greater difficulties in recovery the SCDB unit will investigate the link between bacterial infection and the epigenome. This will allow the development of new therapeutics. Acting promptly against microbe stimulated pathoepigenetic switches the SCDB unit will inhibit and/or prevent latent or chronic infections, autoimmune diseases and microbe-related cancers.
Pathways and regulatory mechanisms involved in establishment, maintenance and expansion of neural progenitors
The SCDB unit is actively exploring the lesion environment on the behaviour of neural stem cells. Several factors such as inflammatory mediators affect the neurogenic areas following brain injury (whether by acute insults or slow progressive neurodegenerative disorders), that results in increased proliferation, abnormal migration and maturation of neural progenitors. Grafted and reprogrammed cells are exposed to the same injury environment as endogenous stem cells within the SCDB unit allowing the unit to study the impact of exposure to these lesion on the survival and differentiation of different sources of neural progenitors or reprogrammed cells. Understanding the mechanisms and signalling events involved in post-injury neurogenesis allows the SCDB unit to identify therapeutic targets to ensure proper brain repair and function restoration after injury.
Characterize the functionality of the intestinal microbiota of diabetic children
Intestinal microbiota are modulated by host genetics, diet, immune system and the interaction between these factors, along with viral infections may lead to the development of beta-cell autoimmunity and the destruction of insulin-producing beta-cells in Langerhans islets. So far the published data on the gut microbiota in humans suffering diabetes type 1 is very limited and needs further research. The SCDB unit has demonstrated that diabetic children possess an intestinal microbiota with different functionality in comparison with control children. The further investigation of this subject will characterize the differences found and to “engineer” a microbiota in order to mount a possible therapeutic intervention (bacteriotherapy).
Differentiation of cardiac/neural progenitors to mature dopaminergic neurons/cardiomyocytes
The SCDB unit will perform direct comparisons of existing differentiation protocols for cardiomyocytes and dopaminergic neurons and integrate the knowledge acquired and methods developed by our unit. The goal will be to further develop differentiation protocols for both cell therapy approaches and disease modelling of Gaucher’s Disease and Fabry Disease.
Gene Expression and Mitosis
The SCDB unit hypothesize that beyond the selective pressure for small transcriptional units, there is also a pressure to avoid pre-mRNA splicing during early zygotic expression, which was a likely explanation why most early zygotic transcripts are intronless. The SCDB unit has isolated two mutant alleles that specifically impair pre-mRNA splicing of early zygotic but not maternally encoded transcripts, and demonstrate the existence of a developmental pre-requisite for highly efficient splicing during early embryonic development. This suggests that highly proliferative tissues need coordination between cell cycle and gene architecture for correct gene expression and avoidance of abnormally processed transcripts. Our results also suggest that the pre-requisite for highly efficient splicing due to the fast mitotic divisions is paradoxically also likely to play an important regulatory role in the expression of a subset of early zygotic transcripts. The SCDB unit will focus on investigating if mitotic down regulation of transcription and pre-mRNA splicing regulates the correct gene expression during fast development, and if such mechanisms, are important for pathological processes associated with uncontrolled cell proliferation.