Researchers have created a way to guide and control the development of stem cells into specific tissues and organs, opening the door to developing a means of one day tackling complex diseases like diabetes and Parkinson’s disease.
Arguably, stem cells represent the future of healthcare and medical research. With the potential to unlock possibilities for healing, understanding, and innovation in ways that traditional approaches can’t, they’re a foundation for how diseases could be treated and prevented and the future.
Now, researchers from Cedars-Sinai Health Sciences University and the University of California, San Francisco (UCSF) have advanced stem cell development further. Their collaboration has resulted in engineered cells called ‘synthetic organizers’ that deliver instructions to stem cells, telling them to grow into specific tissues and organs.
“We can use these synthetic organizers to push the stem cells toward making different parts of the early embryo or toward making a heart or other organs,” said Ophir Klein, MD, PhD, a member of the Cedars-Sinai Regenerative Medicine Institute, director of UCSF’s Institute for Human Genetics, and the study’s co-corresponding author.
Previous research has shown that some cells present during very early development can act as organizers or signalers for in vitro embryos. These cells organize themselves around stem cells, providing them with instructions for their development. With this in mind, the researchers advanced a hypothesis: If they engineered a version of these organizer cells, they may be better able to guide in vitro development.
The researchers took native and synthetic cell adhesion molecules (CAMs), proteins that help cells stick to each other and their surroundings, and engineered organizer cells that self-assembled around mouse embryonic stem cells (mESCs) in customizable architectures. Then, they engineered the cells to produce specific signaling molecules called morphogens.
Morphogens are key to cellular development. They determine a cell’s fate based on their concentration. When morphogens spread out from a source, they form gradients – areas of high concentration closer to the source and lower concentration farther away. Cells ‘read’ these gradients to figure out their position and role in the developing tissue. For example, high levels might tell a cell to become a nerve cell, medium levels tell it to become a skin cell, and low levels might signal a cell to become connective tissue.
The organizer cells were engineered to express the morphogen Wingless-related integration site 3A (WNT3A) and its antagonist Dickkopf-1 (DKK1) in different gradients. This allowed the researchers to explore how changing the gradient guided the embryoid – an aggregate of embryonic stem cells – toward distinct outcomes. They induced the stem cells to begin forming a mouse body from head to tail, similar to how an embryo develops in the womb. In a separate experiment, they instructed the stem cells to form a beating, heart-like structure, complete with a central chamber and a network of blood vessels.
“This type of synthetic organizer cell platform provides a new way to interface with stem cells and to program what they develop into,” said Wendell Lim, PhD, the study’s other corresponding author and a professor of Cellular and Molecular Pharmacology at UCSF. “By controlling and reshaping how stem cells differentiate and develop, it might allow us to grow better organs for transplantation of organoids for disease modeling and eventually utilize it to drive tissue regeneration in living patients.”
The engineered organizer cells were also fitted with a chemical switch that enabled the researchers to turn the delivery of cellular instructions on and off, as well as a ‘suicide switch’ for eliminating the cells when needed.
“These synthetic organizers show that we can provide more refined developmental instructions to stem cells by engineering where and when specific morphogen signals are provided,” Lim said. “The organizer cells carry both spatial information and biochemical information, thus giving us an incredible amount of control that we have not had before.”
Technology like this has the potential to lead to tremendous real-world applications in regenerative medicine, personalized medicine, drug development and testing, a greater understanding of human development, and treating chronic and genetic conditions.
“The remarkable science of programming instructions to coax stem cells could one day open the door to tackle complex diseases,” Klein said. “We could generate specific cell types, like a beta cell to make insulin or a neuron to treat Parkinson’s disease, within the context of a large piece of tissue or even a whole organ. This work opens many new and exciting possibilities.”
The study was published in the journal Cell.
Source: Cedars-Sinai
