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Layers of complexity: differentiating iPSCs into derivatives of the embryonic germ layers

Cell Culture Specialist Team

Layers of complexity: differentiating iPSCs into derivatives of the embryonic germ layers

Through the previous blogs in this series, we have understood the challenges which somatic cells face when changing their career path to become induced pluripotent stem cells (iPSCs), the ways in which we can induce this change , and how we might assess whether this is the right career for the cells through pluripotency and differentiation assays .

Now that we have the iPSCs, how do we encourage a pluripotent cell line into a specific tissue type derived from one of the three germ layers, ensuring that we maximize a cell’s career potential? In this blog we will delve in and discuss how this is possible.

The Origin of Somatic Cells

Somatic cell reprogramming offers huge potential for disease modelling, drug discovery, drug development, regenerative medicine and cell therapy. Following the generation of iPSCs, various growth factors or small molecules can be used to drive the formation of a multiplicity of cell types. Optimization of these methods has been the focus of the many research groups endeavoring to develop robust and reproducible methods of differentiation. But where do these valuable career-changing cells originate from?

To answer this question, we must consider the germ layers. These are three distinct layers of cells produced during the gastrulation stage of mammalian embryonic development, which give rise to every organ and tissue within the body. All animals, including humans, form three germ layers, known as the ectoderm, endoderm and mesoderm. Different cell lineages evolve from each layer, resulting in mature somatic cells which perform organ- or tissue-specific functions. The iPSCs generated by reprogramming these mature somatic cells have the capacity to develop into cells from all three germ layers.

The ectoderm: potential is not only skin deep

The ectoderm is the outermost of the three germ layers. It gives rise to many outer regions of the body such as the epidermis, hair, nails, mouth epithelium, cornea and olfactory epithelium. The central and peripheral nervous systems are also derived from the ectoderm.

Differentiation of iPSCs into the embryonic ectoderm and its derivatives has huge potential in wound healing. A 2015 study by Zhang et al differentiated iPSC into mesenchymal stem cells (MSC), which are well-documented as being key players in repairing and regenerating damaged tissue. MSC can develop into bone, cartilage, and fat cells, and are employed in many current stem cell therapies focused toward healing.

Following characterization by flow cytometry for surface markers including CD29, CD73, CD90, CD34, CD45, HLA-DR, the authors generated exosomes from the MSC. These were subsequently injected around wound sites in a rat model, where they were shown to facilitate wound healing through promotion of collagen synthesis and angiogenesis.

The endoderm: filling the viscera

The endoderm is the innermost germ layer, from which many of the internal linings of the body are derived. These include those of the gastrointestinal tract, lungs, liver and pancreas.

Cells derived from the endoderm offer therapeutic potential for conditions including diabetes and liver failure, yet the generation of such cells is technically challenging. At present few protocols produce functionally relevant mature, adult cells. A 2014 study by Takeuchi et al showed promise in the generation of insulin producing cells (IPCs), which represent a valuable tool for cell therapy and drug discovery in diabetes. The authors established a robust method of producing mature iPCs via induction of DAZL-expressing (DE) cells and then PDX11 cells, which secreted insulin in response to glucose stimulation in 3D culture.

The mesoderm: the potential within

The mesoderm lies between the ectoderm and the endoderm, and from this all other tissues of the body are formed. These include the dermis, heart, muscles, bones, bone marrow and the blood.

iPSC differentiation into cell types formed from the mesoderm has been studied across many research fields. Cardiomyocytes and kidney proximal tubules offer translational models for toxicity studies , while endothelial colony forming cells (ECFCs) are ideal for furthering our understanding of angiogenesis and tumor vascularization . A 2017 study by Zuppinger et al demonstrated the translational potential of iPSC-derived cells by reporting that the proteins expressed by primary cardiomyocytes matched those expressed by Axol’s ventricular cardiomyocytes following ten days in culture . Axol’s cardiomyocyte cells are a highly pure population, expressing a range of ventricular cardiomyocyte markers. Furthermore they exhibit appropriate action potential pharmacology of the three core cardiac ionic currents (I Na , I CaL , and I Kr ) for physiologically relevant drug safety testing.


Encouraging somatic cells to make a career change into differentiated iPSC-derived cells has the potential to push your research onto new and novel applications, enhancing your drug discovery, drug development or your understanding of a biological mechanism or system.

Take advantage of this potential through Axol Bioscience. We offer a comprehensive range of iPSC-derived cells along with expertly optimized growth media for their successful culture and propagation, and we also supply differentiated cells derived from healthy donors and patients of specific disease backgrounds. Our expertise includes reprogramming cells to iPSCs and differentiating them to various cell types. Through our custom service offerings, we can also take cells provided by you and carry out the reprogramming and differentiation, saving you both time and money.

view our custom stem cell differentiation service

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