DNA sample being pipetted into petri dish with DNA gel in background

Stem Cell & Regenerative Neuroscience

Contact

Jefferson Stem Cell & Regenerative Neuroscience Center

900 Walnut Street, Room 461
Jefferson Hospital for Neuroscience
Philadelphia, PA 19107

Research

Stem cells are distinguished by their ability to divide infinitely as unspecified cells while still maintaining the capacity to differentiate and form the specialized cells that make up our blood, skin, muscles, tissues, and organs. These qualities of self-renewal and unlimited potential makes stem cells a desirable tool for both research and medicine. In the early 21st century, to avoid the legal and ethical issues surrounding embryonic stem cells, scientists sought to find a source of stem cells independent of the use of embryonic tissue. This endeavor led to the development of induced pluripotent stem cells, coined iPS cells, from adult human cell types.

In 2008, Shinya Yamanaka at Kyoto University in Japan was the first scientist to show that adult human fibroblasts derived from routine skin biopsy could be induced to become stem cells. By “infecting” the fibroblast cells with a virus that contained key stem cell-associated genes, the cells were rapidly reprogrammed into induced pluripotent stem cells (iPS cells). The following year, it was discovered that many other human and mammalian cell types could also be used for reprogramming, including: blood cells, hepatocytes, keratinocytes, and lymphocytes. Four years later, Shinya Yamanaka was awarded the Nobel Prize for his contribution to the discovery of iPS cells.

Following the development of iPS cells, rapid advances were made in the methods used to reprogram, characterize, maintain, and differentiate iPS cells. In reprogramming, the original viruses used to reprogram iPS cells were replaced by safer and more efficient methods. Stringent criteria has been put in place to characterize and verify the pluripotency and general quality of the iPS cells. The methods used to carry iPS cells in a state of pluripotency for long stretches of time were refined and optimized. Finally, the differentiation of iPS cells, whereby iPS cells can be influenced to become specialized cell types such as neuronal subtypes, muscle, retinal pigment epithelium, and hepatocytes established itself as a dynamic new technology for the study and treatment of disease.

With these advances in iPS cell technology, the vision of creating personalized disease models and therapeutics, becomes a reality. Patient samples including skin, blood, urine, and hair can be collected and reprogrammed to create iPS cell lines unique to the individual with the hope of understanding the unique disease mechanisms of individual patients. Sister lines genetically modified with CRISPR-cas9 to exclude genes linked to disease can be studied alongside their diseased line. The future for iPS cell technology includes:

Autologous cell replacement made possible by patient-specific cells.
Disease modeling in cells carrying the genetic signature of disease (Parkinson’s Disease, ALS, Alzheimer’s Disease, etc.)
High throughput screening for drug discovery and development using human cells with disease.
Addition of therapeutic genes using gene editing for cell replacement therapies.

Research of Labs Working with the JSCRNC

Ya-Ming Hou, PhD

The Hou Lab will use the iPSC lines produced from the core facility to study the disease mechanism of Charcot-Marie-Tooth (CMT) disease associated with the R329H mutation in alanyl-tRNA synthetase (AARS). CMT is the most common peripheral neuropathy, affecting one in 2500 individuals worldwide and impairing the mobility of extremities in the patient, such as hands and feet. We will test the hypothesis that the AARS mutation, which reduces tRNA charging, decreases the synthesis of axonal proteins required for neuron function.

Lorraine Iacovitti, PhD

The Iacovitti Lab uses human induced pluripotent stem (hiPS) cells carrying the genetic signature of Parkinson’s Disease (PD) to investigate the cause of PD, the second most common neurodegenerative disease affecting millions of patients globally. Current research studies in the lab include the effects of PD gene mutations on midbrain dopamine (mDA) neuron survival and function as well as the ways in which mDA neurons carrying PD genes interact with their environment. Future aims for hiPS cell-derived mDA neurons include the use of these neurons to screen potential new pharmaceutical and cell-based therapies.

Jefferson Weinberg ALS Center

The Jefferson Weinberg ALS Center is interested in using the iPSC lines produced by the core facility to develop motor unit models to study Amyotrophic Lateral Sclerosis (ALS). We aim to use our models to study various pathogenic mechanisms behind the multiple disease-causative mutations.

Diane Merry, PhD

The Merry lab will use human induced pluripotent stem (hiPS) cells derived from patients with genetic neurological disorders, including the protein misfolding diseases spinal and bulbar muscular atrophy (SBMA) and Huntington’s disease, as well as inherited forms of autism spectrum disorder (ASD). Various cell types, but primarily neurons, differentiated from relevant cell lines and controls will be used to understand the role of molecular pathogenic mechanisms implicated through our studies using other cell and animal models. In addition, we will carry out transcriptomic and proteomic analyses of hiPS cell-derived neurons and other cell types, including muscle, to identify novel pathways that contribute to pathogenic mechanisms.

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