Tunable hydrogels guide stem cell differentiation

Differentiating stem cells into mature cells of adult tissue involves many intricate steps to get them to develop into the right cell types. You could compare the process to the careful adjustments you make when tuning a guitar.

In the body, stem cells receive cues from their surrounding environment to mature into specific types of cells. These cues can be biochemical – molecules like lipids, growth factors and metabolites (products of cell metabolism) – or they can be physical – the stiffness of surrounding tissue. But these molecules and structures aren’t always present when scientists attempt to differentiate stem cells outside the body, say in a cell culture dish.

One way researchers are improving the methods for differentiating stem cells outside the body is by using biomaterials such as hydrogels that mimic properties of the structures and molecules found naturally in various stem cell niches that aid in their maturation to adult cell types.

A CIRM-funded study published last week in the journal Chem, has developed “tunable hydrogels” that direct stem cells to differentiate into brain, cartilage and bone cells based on adjustments to the hydrogel’s stiffness and metabolite profile. The work was a collaboration between scientists in New York and in Scotland and one of the co-authors, Bruno Péault, was a CIRM-funded scientist in California during the time of the study.

Hydrogels with different stiffness' direct stem cells to differentiate into different types of tissue. (Chem)

Hydrogels with different stiffness’ direct stem cells to differentiate into different types of tissue. (Chem)

Tuning gels to differentiate stem cells

The scientists started with hydrogels composed of nanofibers that varied in stiffness and observed that perivascular stem cells (from the connective tissue surrounding blood vessels) grown in more flexible gels turned into brain cells and those that were grown in stiffer gels turned into bone cells. The stiffness of these different hydrogels was comparable to that of actual brain and bone tissue, which indicated that stiffness is important for stem cell fate.

But stiffness alone isn’t responsible for directing stem cells into different cell fates – biochemical metabolites are also key to this process. The authors also analyzed the metabolite profiles of the different hydrogels to determine which metabolites were important for stem cell differentiation. They tested different concentrations of over 600 metabolites in the hydrogels during stem cell differentiation and found that certain lipids like lysophosphatidic acid and cholesterol sulfate were essential for differentiation into cartilage and bone tissue respectively. When these specific lipids were added to regular stem cell cultures (without hydrogels), the stem cells differentiated towards cartilage and bone cells. Thus they concluded that both the metabolite profile and the stiffness of hydrogels are important for directing stem cell differentiation.

Interestingly, the authors also showed how metabolites like cholesterol sulfate could influence and activate transcription factors – proteins that also direct stem cell differentiation – which controlled the activation of bone-related genes. This finding suggests a relationship between metabolite expression and transcription factor activity and offers a simpler way to activate transcription factors important for stem cell fate.

Big picture of tunable hydrogels

Looking at the big picture, this study offers a useful strategy to identify molecules that promote formation of specific tissue types from stem cells. These molecules could be potential drug candidates that could aid in regenerating bone and cartilage tissue for patients with osteoporosis or osteoarthritis.

Co-senior author on the study and professor at the University of Glasgow, Matthew Dalby, who was interviewed by Science Magazine elaborated on the importance of their study:

Matthew Dalby

Matthew Dalby

“Our ambition is to simplify drug discovery — by using the cell’s own metabolites as drug candidates. For example, cholesterol sulfate, which our rigid gel revealed as critical to bone cell differentiation, could be a safer solution (e.g., minimal off-target effects) for treating osteoporosis, spinal fusion, and other bone-related conditions. Presently, growth factors are used, but these can lead to unwanted collateral damage, and government agencies in the UK and US have published warnings against their use.”

Rein Ulijn, co-senior author with Dalby and professor at the City University of New York and University of Strathclyde, concluded by emphasizing how the metabolites they identified could be potential drug candidates and would pass regulatory approval if shown to be safe and effective:

Rein Ulijn

Rein Ulijn

“That you can use simple metabolites like cholesterol sulfate, which is readily available, to induce differentiation is in my view very powerful if you think about this as a potential drug candidate. These metabolites are inherently biocompatible, so the hurdles to approval are going to be much lower compared to those associated with completely new chemical entities.”

In the future, both teams plan to further “tune” their hydrogels to mimic more complex tissue environments that incorporate additional properties besides stiffness in hopes of creating more relevant 3D micro-environments to model the stem cell niche.

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