Building Flesh and Blood

The ability to engineer blood vessel networks is one of the most important hurdles standing between the present state of the art in tissue engineering and the creation of large, functional tissue masses. Tissue of any meaningful size requires an intricate web of tiny blood vessels to support it, and that network must be tied into existing blood vessels in the body. The need for blood vessels is one of the reasons why decellularization of donor organs is a useful strategy at the present time: the extracellular matrix stripped of donor cells supplies the needed blood vessel structures, complete with chemical cues to guide new cells into the right places to reform the vessels.

In the case of organ engineering, one major obstacle keeping researchers from crafting functioning organs is the inability to ensure adequate blood supply to the nascent organ. Even if an entire organ can be constructed using all the appropriate cell types, its survival in the body depends on its access to oxygen and nutrients. Thin layers of tissue such as cartilage can get by with the simple diffusion of these life-giving compounds across tissue boundaries and do not require the construction of blood vessels to survive once implanted in a body. But more complex engineered tissues and organs require functional blood vessels to deliver oxygen and nutrients and to remove waste products.

But engineering functional blood vessel networks is not an easy task. Researchers must understand the mechanisms that drive the formation of blood vessels in order to guarantee consistent results and optimal survival of engineered tissues and organs. How do endothelial cells self-organize into functional networks? Do the cells require external cues to form stable vessels? How do they interact with neighboring cells to ensure expedient microvessel formation?

In 2008 [researchers] found that combining mesenchymal stem cells (MSCs) from human bone marrow with human endothelial cells prompted the formation of robust vascular networks. In some ways, this was a bit surprising, because the added stem cells were not really functioning in a typical stem-cell capacity. They were not differentiating into endothelial cells, nor were they being converted into the cell types that MSCs normally give rise to, such as bone, cartilage, or fat. Instead, they were somehow acting as "builders" to help organize the "building blocks" - the endothelial cells - into a functional network.

Recent work suggests that the interaction between [MSCs] and endothelial cells may also apply to blood-vessel cells derived from human induced pluripotent stem cells (iPSCs). [Human] iPSCs can generate both endothelial cells and pericytes, and that combining such iPSC-derived cells creates robust vessels. Because iPSCs can be derived from individual patients and tailored to their specific needs while minimizing the risk of immune rejection, this approach may help equip made-to-order iPSC-derived organs with the iPSC-derived blood vessels they need to survive.



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