Stem Cells on my Mind

Calling the brain complex is an understatement. Consisting of 100 billion neurons, each of which is connected to as many as 10,000 other neurons, we are just starting to unravel the many functions of the brain in health and disease. One obstacle to studying the brain and developing treatments for its many diseases is the fact that neurons, like cardiomyocytes, don’t divide. The brain is incredibly plastic and is capable of forming new connections between existing neurons, but they don’t proliferate which makes them difficult to study in the lab. Much research has been done using mouse cells, but for a long time there wasn’t a good way to study human microglial cells. Recent research has focused on reprogramming already differentiated skin cells (“fibroblasts”) into a variety of neural cell types. These techniques can help us better understand the brain, and maybe even treat some of its most devastating diseases.

Microglial Cells: Custodians of the Brain

Microglial cells are a type of immune cell found in the brain. They are crucial when it comes to brain development, plasticity, and maintaining the proper conditions for neurons to function. Additionally, they have been found to play a role in the progression of diseases, such as Alzheimer’s disease. These progressive neurodegenerative diseases are difficult to study in animal models, partly due to differences in biology and partly due to the fact that they develop after many decades. A recent paper published by Abud et al. [1] was able to create microglial cells from humans using induced pluripotent stem cells (iPSCs). The researchers took samples of skin and blood cells from human donors and reprogrammed them into iPSCs. They then used a differentiation protocol they developed using a specific combination of proteins, hormones, and other soluble factors to guide the iPSCs into forming microglial cells. These cells resemble native microglial cells in many ways and naturally integrate into the 3D structure of both brain organoid structures (Fig. 1) and in vivo in the brains of mice.

Figure 1: 3D brain organoid tissue. Microglial cells (green) spread throughout a 3D brain organoid tissue in a dish. Blue indicates a structural protein representing neurons and red indicates astrocytes, another type of support cell in the brain. (Credit: Abud et al.)

New Treatments for Brain Cancer

                  Cancers of the brain, such as glioblastoma, are devastating. They are difficult to treat, and the side effects of treatment, including chemotherapy and surgery, can be as difficult to deal with as the cancer itself. Finally, glioblastoma progresses extremely quickly and the average survival is only about a year. New treatments to improve survival and lessen side effects are desperately needed. Several years ago, researchers discovered that neural stem cells will migrate to sites of glioblastoma. They can be engineered to produce various proteins that will kill the cells nearby, which makes this an attractive method for non-invasively treating brain cancer. However, native neural stem cells are difficult to find. Until now, researchers had to reprogram cells into iPSCs which could then be differentiated into neural stem cells, a time-consuming process. In a recent paper, Bagó et al. developed a streamlined process for producing patient-specific neural stem cells [2]. They directly differentiated (transdifferentiated) skin cells from human donors into neural stem cells, using one of the 4 factors needed to create iPSCs. By skipping the iPSC step, they can create neural stem cells in only 4 days. This speed is critical when it comes to a fast-moving cancer like glioblastoma. The neural stem cells they created were engineered with a protein to kill the cancer cells and they cells migrated to the site of glioblastoma and slowed the progression of tumor growth (Fig. 2).

Figure 2: A mouse model of glioblastoma. In mice treated with the control cells (top row), tumors grew significantly over 20 days (red). In the treatment group (bottom row), the tumor growth was greatly inhibited. (Credit: Bagó et al.)

                  Considering how unique our brains are to making us who we are, it makes sense that it would be one of the first areas to benefit from the development of personalized medicine. In time, we may come to a deeper understanding of one of nature’s greatest mysteries, and the possibilities are mind-boggling.

[1] Abud EM, Ramirez RN, Martinez ES, Healy LM, Nguyen CHH . . . Blurton-Jones M. (2017).  iPSC-Derived Human Microglia-like Cells to Study Neurological Diseases. Neuron.

[2] Bagó JR, Okolie O, Dumitru R, Ewend MG, Parker JS . . . Hingtgen SD. (2017). Tumor-homing cytotoxic human induced neural stem cells for cancer therapy. Science Translational Medicine.