Stem cell bioengineering: building from stem cell biology


New fundamental discoveries in stem cell biology have yielded potentially transformative regenerative therapeutics. However, widespread implementation of stem-cell-derived therapeutics remains sporadic. Barriers that impede the development of these therapeutics can be linked to our incomplete understanding of how the regulatory networks that encode stem cell fate govern the development of the complex tissues and organs that are ultimately required for restorative function. Bioengineering tools, strategies and design principles represent core components of the stem cell bioengineering toolbox. Applied to the different layers of complexity present in stem-cell-derived systems — from gene regulatory networks in single stem cells to the systemic interactions of stem-cell-derived organs and tissues — stem cell bioengineering can address existing challenges and advance regenerative medicine and cellular therapies.

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Fig. 1: The stem cell hierarchy.
Fig. 2: Layers of complexity in stem cell systems.
Fig. 3: Stem cell bioengineers apply engineering design principles to overcome barriers in stem cell research.
Fig. 4: Feedback regulation in stem cell systems provides robust control of system dynamics.
Fig. 5: Reverse and forward engineering strategies are used to map and manipulate the stem cell gene regulatory network.
Fig. 6: A combined computational modelling and bioreactor design strategy enables enhanced expansion of haematopoietic stem cells.
Fig. 7: Niche engineering by micropatterning of cells to control colony shape and size.
Fig. 8: Microfluidics technologies enable organ-on-a-chip and human-on-a-chip applications.


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The authors thank C. Bauwens for her insightful feedback on this review. The authors especially thank D. Lauffenburger (Massachusetts Institute of Technology), a strong proponent of the cue–signal–response paradigm and with whom P.W.Z. has had many helpful discussions on the engineering approach to biology over the years. The authors apologize to their colleagues whose important work could not be included because of space constraints. The authors are funded by the Canadian Institutes for Health Research and Medicine by Design, a Canada First Research Excellence Programme at the University of Toronto. P.W.Z. is the Canada Research Chair in Stem Cell Engineering.

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Nature Reviews Genetics thanks D. V. Schaffer and the other anonymous reviewer(s) for their contribution to the peer review of this work.

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The authors contributed equally to all aspects of the article.

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Correspondence to Peter W. Zandstra.

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Cell therapies

Clinical treatments that introduce living cellular material into a patient. They may engraft in the body, leading to long-term replacement of damaged or missing tissue, or stimulate endogenous repair and promote endogenous viability.

Embryonic stem cell

(ESC). A type of pluripotent stem cell, derived from the inner cell mass of the developing embryo, that is responsible for giving rise to all of the cells in the developing fetus but not the extra-embryonic tissues.


A minimal and miniaturized organ that is developed from a suspension of stem cells in vitro. These stem cells undergo division and self-organization to give rise to a 3D structure that mimics the anatomy of organs in the body. Thus, organoids can serve as models for understanding organ development and for modelling disease states.

Cell fate

A cell’s identity based on its expression of genetic, proteomic and epigenetic markers but also in terms of its functional abilities. Cell fate determines a cell’s self-renewal ability, proliferative ability, differentiation potential, survival and motility.


A form of cellular signalling in which secreted chemicals bind to receptors on the same cell. By contrast, juxtacrine and paracrine signalling induce responses in neighbouring cells, either through direct contact (juxtacrine) or secreted chemicals (paracrine).

Extracellular matrix

(ECM). A collection of extracellular molecules, including proteins, proteoglycans and polysaccharides, that supports the growth of nearby cells by providing biomechanical and biochemical cues. It enables cell adhesion and cell–cell communication.

Gene regulatory networks

(GRNs). A set of genes and their direct and indirect regulatory interactions with one another. GRNs are akin to decision-making computational circuits that serve to process input signals and generate robust outputs in cell behaviour.

Network motifs

Interaction patterns that recur more frequently than in randomized networks — for example, negative autoregulation (or ‘autorepression’) and the feedforward loop.


The in vivo microenvironments in which stem cells reside that regulate their homeostasis and fate choices.


The process by which developing organisms acquire their structure and shape.

Bayesian networks

Probabilistic models that relate the dependencies of the expression of a set of genes on one another through a directed graph.

Boolean networks

Models of gene regulatory networks that can predict gene expression outcomes given the initial state of genes in the network as well as the derivation of steady-state gene expression status.

Artificial neural networks

Networks composed of nodes, which can be genes, that process and transmit information. The output of each node is a nonlinear function of a sum of its regulatory inputs.

Ordinary differential equations

A mathematical framework capturing gene expression dynamics as a function of the presence of regulators and the rate of change of mRNA and/or protein concentration due to production and degradation.

Reverse engineering

The process of analysing a system to uncover underlying design rules to create representations of the system at higher levels of abstraction (inverse of forward engineering).

Forward engineering

The iterative process by which a system is designed, prototyped, tested and further optimized from a model (the classical engineering design process).


Technology that enables transfer of miniature ‘islands’ of extracellular matrix proteins to enforce control of the shape and size of adherent cells either as single cells or cell colonies.


The characteristic of a cell that makes it a stem cell. That is, the ability to self-renew and differentiate to specify to different cell types.


Vessels in which biological species, such as stem cells and their progeny, are grown, maintained and manipulated in a controlled environment (pH, oxygen and media change) for cell manufacturing pipelines.


Utilization of printing techniques ranging from inkjet printers to 3D printers to combine cells, biomaterials, extracellular matrix, growth factors, etc. to fabricate complex tissue surrogates in vitro.

Fate patterning

A process during embryogenesis in which cell fates are allocated or ‘patterned’ as a function of space and time.


Signalling molecules, typically soluble chemicals, for which the asymmetric distribution in a developing tissue gives rise to fate patterning and morphogenesis.

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Tewary, M., Shakiba, N. & Zandstra, P.W. Stem cell bioengineering: building from stem cell biology. Nat Rev Genet 19, 595–614 (2018).

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