Stem cell production: boosting applications in cellular and gene therapy

The Stem Cell Engineering Research Group, Institute for Bioengineering and Biosciences, focuses on the development of cell production systems for the ex-vivo expansion on stem cells.

The Stem Cell Engineering Research Group at Institute for Bioengineering and Biosciences, Lisbon, Portugal, relies on a cross-disciplinary strategy combining bioprocess engineering with stem cell biology, focusing on six major research themes.

The Stem Cell Engineering Research Group (SCERG)’ focuses on the development of cell production systems for the ex-expansion of stem cells and/or their controlled differentiation into specific cell types, alongside their integration with bioseparation and high resolution purification technologies. This in order to generate the large numbers of specific and high quality stem/progenitor cell subsets needed for precision and regenerative medicine settings.

SCERG has established an international track record in the Stem Cell Engineering field, as assessed by WTEC in the USA on behalf vivo of NSF, NIST and NIH. The success of stem cell manufacturing relies on safe, robust and reproducible culture conditions and cost-effective processes, including bioreactor design, bioseparation, microscale technology and process control, combined with systems biology. The development of efficient, scalable and cost-effective production processes for stem cells is expected to boost their applications in cellular and gene therapy, tissue engineering, high-throughput drug screening, toxicological testing and stem cell research.

Human hematopoietic stem/progenitor cells and mesenchymal stem/stromal cells, as well as human pluripotent stem cells (both embryonic stem cells and induced pluripotent stem cells) and their neural and cardiac derivatives have been used as model systems. SCERG relies on a cross-disciplinary strategy combining bioprocess engineering with stem cell biology, focusing on six major research themes which are outlined below.

Bioreactor and microcarrier technologies for stem cell expansion and differentiation

With Joaquim Cabral as research theme leader, SCERG has greatly expanded the understanding of stem cell expansion and differentiation in bioreactors and pioneered the use of microcarrier technology for multipotent, and pluripotent stem cells. Animal-free microcarrier-based stirred culture systems envisaging xeno-free culture systems for scalable cell production, have been established for human mesenchymal stem/stromal cells, and human induced pluripotent stem cells. Large-scale expansion and differentiation of stem cells in controlled microcarrier-based bioreactors are addressed. The operation of novel disposable bioreactors, with low shear stress has been optimised for the scalable xeno-free microcarrier-based cultivation of hiPSC.

Clinical manufacturing of stem cell-based therapies

The robust and scalable cell manufacturing towards the cost-effective delivery of safe and potent cell-based products (either autologous or allogeneic) relies on process engineering tools to understand the impact of cellular features (such as biological and biochemical) on cell product function and performance, and how do process variables influence the critical quality attributes of the cell product. At SCERG, Cláudia Lobato da Silva and her team are developing the innovative manufacturing of two ex-vivo expanded cell-based products:

  • Umbilical cord blood (UCB)-derived hematopoietic stem/progenitor cells for potential application in hemato-oncological settings, and
  • Mesenchymal stem/stromal cells (MSC) from different tissue sources for immunomodulation-based therapies.

Bioprocessing of human pluripotent stem cells for regenerative and precision medicine

The development of integrated bioprocesses is a crucial demand to overcome the main technological barriers that presently limit the application of human Pluripotent Stem Cells (PSC), embryonic (ESC) and induced pluripotent (iPSC), and their derivatives in Regenerative and Precision Medicine. This progress is expected to leverage the emergence of alternative therapies and the development of new personalised tissue models for disease modelling and drug discovery. Bioprocessing approaches that are being developed at SCERG by Maria Margarida Diogo and her research group include:

  • Scalable expansion of hiPSC while maintaining their pluripotency
  • Scalable integrated expansion and controlled neural and cardiac differentiation of hiPSCs by culturing these cells as 3D aggregates in suspension
  • Downstream processing methodologies for hiPSC and their differentiated derivatives and their integration with the scalable expansion and differentiation of hiPSC, and
  • Development of standardised culture platforms for production of neural and cardiac tissues from healthy and patient-specific hiPSCs for disease modelling and drug screening.

Gene delivery strategies to modulate stem cell function

At SCERG, Gabriel Monterio leads her group in the gene induced modification of human mesenchymal stem/stromal cells (MSC) is pursued towards the maximisation of the expansion and differentiation potential of these cells (including the improvement of their intrinsic therapeutic features). In this context, an ex-vivo gene therapy strategy is envisaged to engineer MSC from different human sources with minicircles in order to secrete modulating proteins and exosomes that will alter the behaviour of targeting cells. Minicircle non-viral vectors are rationally engineered to increase ex-vivo MSC transfection, extend transgene expression and facilitate purification. Additionally, the composition of the cell secretome that contains several types of signaling molecules (including microRNAs) may be modified by minicircle-encoded genes and used to alter the response of target cells.

Designing biomaterials and devices for stem cell engineering

The research group led by Frederico Ferreira at SCERG aims to develop and apply tailor-made platforms, comprising engineered biomaterials and designed devices, in the field of regenerative and precision medicine. Synthetic, natural and hybrid polymers have been used in the construction of scaffolds to provide cues to direct cell organisation and function. Additionally, we also aim to develop polymeric matrices able to provide time dependent stimuli to the cells at physiologic conditions. Devices are being designed and prototyped to control hydrodynamic and mechanic stimuli to cells cultured on scaffolds. We are particularly interested in the use electrically conductive polymers to provide electrical stimulation to cells, promoting cell differentiation, organisation and communication. Decellularisation strategies are also being developed to produce acellular bioscaffolds for tissue engineering settings, including the use of bioscaffold-derived soluble products.

Stem cell biosystems engineering

Stem cell biosystems engineering is an innovative approach for studying the mechanisms that modulate the pluripotency of human stem cells and aims at contributing to a better understanding of the molecular and cellular events that regulate stem cell function. As model systems, the research group led by Tiago Fernandes employs in vitro platforms in order to study the cellular events involved in lineage commitment and further maturation of stem cells. The ultimate goal is to develop predictive models of signalling networks from such raw data, study the dynamic regulation of pluripotency circuit components, and gain new insights into the regulatory mechanisms underlying multilineage cell specification, ultimately enabling novel tools for regenerative and precision medicine, including stem cell-based therapies, and therefore positively impacting health and welfare.

Joaquim Cabral
Stem Cell Engineering Research Group
Institute for Bioengineering
and Biosciences
+351 218 419 063

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