Steady and Incremental Progress in Controlling Cells

A broad range of future medicine will be based on ways and means of ever more precisely controlling cells. Many scientists are engaged in the process of developing the necessary knowledge and tools: finding out how to instruct cells to take particular actions, change their internal state, or even shift between cell types; understanding cellular processes well enough to be able to adjust or repair them when they are broken; learning how to steer vast numbers of cells in the collaborative work of maintaining tissue function and building new tissue. Progress is incremental, as there are hundreds of different cell types in the body and while they are all built on the same chassis, as it were, they are nonetheless very different from one another. Specialist research groups tend to work with just a few types of cell, making small steps forward year after year in understanding cell signals and behaviors well enough to manipulate them.

The recent research publicity releases quoted below are examples of the sort of work that will be taking place for decades yet. This is the foundation of regenerative medicine: the small projects and narrowly focused advances that will together form the basis for future therapies. It's a lot of work, as cell biology is enormously complex.

A step closer to artificial livers

The liver can indeed regenerate itself if part of it is removed. However, researchers trying to exploit that ability in hopes of producing artificial liver tissue for transplantation have repeatedly been stymied: Mature liver cells, known as hepatocytes, quickly lose their normal function when removed from the body. "It's a paradox because we know liver cells are capable of growing, but somehow we can't get them to grow" outside the body.

Now, [researchers] have taken a step toward that goal. [They] previously developed a way to temporarily maintain normal liver-cell function after those cells are removed from the body, by precisely intermingling them with mouse fibroblast cells. For this study, [the] research team adapted the system so that the liver cells could grow, in layers with the fibroblast cells, in small depressions in a lab dish. This allowed the researchers to perform large-scale, rapid studies of how 12,500 different chemicals affect liver-cell growth and function. [After] screening thousands of liver cells from eight different tissue donors, the researchers identified 12 compounds that helped the cells maintain those functions, promoted liver cell division, or both.

Two of those compounds seemed to work especially well in cells from younger donors, so the researchers [also] tested them in liver cells generated from induced pluripotent stem cells (iPSCs). Scientists have tried to create hepatocytes from iPSCs before, but such cells don't usually reach a fully mature state. However, when treated with those two compounds, the cells matured more completely. [Other] researchers are now testing them in a variety of cell types generated from iPSCs. In future studies, [the] team plans to embed the treated liver cells on polymer tissue scaffolds and implant them in mice, to test whether they could be used as replacement liver tissues. They are also pursuing the possibility of developing the compounds as drugs to help regenerate patients' own liver tissues.

Penn Research Shows Way to Improve Stem Cells' Cartilage Formation

"The broad picture is trying to develop new therapies to replace cartilage tissue, starting with focal defects - things like sports injuries - and then hopefully moving toward surface replacement for cartilage degradation that comes with aging. Here, we're trying to figure out the right environment for adult stem cells to produce the best cartilage. As we age, the health and vitality of cartilage cells declines, so the efficacy of any repair with adult chondrocytes is actually quite low. Stem cells, which retain this vital capacity, are therefore ideal."

The first step in growing new cartilage is initiating chondrogenesis, or convincing the mesenchymal stem cells to differentiate into chondrocytes, which in turn generate the spongy matrix of collagen and sugars that cushions joints. One challenge in prompting this differentiation is that, despite the low density of adult chondrocytes in tissues, the actual formation of cartilage begins with cells in close proximity. "In typical hydrogels used in cartilage tissue engineering we're spacing cells apart, so they're losing that initial signal and interaction. That's when we started thinking about cadherins, which are molecules that these cells use to interact with each other, particularly at the point they first become chondrocytes."

To simulate that environment, the researchers used a peptide sequence that mimics these cadherin interactions, which they bound to the hydrogels used to encapsulate the mesenchymal stem cells. "While the direct link between cadherins and chondrogenesis is not completely understood, what's known is that if you enhance these interactions early during tissue formation, you can make more cartilage, and, if you block them, you get very poor cartilage formation. What this gel does is trick the cell into thinking it's got friends nearby."

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