MCAT Biological and Biochemical Foundations of Living Systems: Passage 9 — Flashcards

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Although common neurological diseases, such as Alzheimer's, Parkinson's, and amyotrophic lateral sclerosis (ALS), have distinct symptoms and molecular mechanisms, they share one important feature: they all involve the death of neuronal cells. In the case of Alzheimer's, cell death occurs in the brain and is nonspecific, whereas with Parkinson's and ALS, it is limited to dopaminergic neurons and motor neurons, respectively. Nevertheless, because the pathologies of these diseases all lead to the destruction of nerve cells, stem cell–based regeneration has the potential to be effective against all of them. Stem cells are defined by two important properties: their potential to proliferate and to differentiate into multiple cell types. They can be derived from embryonic tissue (embryonic stem cells [ESCs]) and fetal tissue (fetal stem cells [FSCs]). However, ESCs and FCSs face a number of complications, particularly ethical concerns and questions about tumor formation and immune rejection after transplantation. In 2006, researchers made a potential breakthrough in stem cell therapy when they demonstrated that c-Myc, Sox2, Oct4, and Klf4 could reprogram somatic cells into a state of pluripotency. Nevertheless, the induction of pluripotency is an inefficient process, and the requirement to overexpress c-Myc and the other factors similarly raised concerns about tumor formation as a potential adverse side effect. An alternative source of stem cells is self-renewing cells that reside in the epithelial lining of skin, stomach, intestine, and other tissues and that help replenish the tissue after exposure to environmental insults. These cells are referred to as adult stem cells (ASCs), and they are multipotent, meaning that they can differentiate into all of the cell types of their resident tissue. ASCs do not present the same ethical dilemma as ESCs and FSCs and may solve concerns of immune rejection if autologous transplants are used. As a result, much work has been devoted to characterizing the biomarkers found on the surface of ASCs to understand and isolate these cell populations. Yet ASCs still present challenges, such as difficulty harvesting, poor proliferation, and limited differentiation. One type of ASCs, mesenchymal stem cells (MSCs), has the advantage of being relatively easy to isolate from samples such as the spinal fluid or umbilical cord blood, and they also expand well in tissue culture. In addition, it has been demonstrated that MSCs not only differentiate into bone, cartilage, and adipocyte cells but could also give rise to a variety of other cell types, including neurons. Once in the body, the localization of MSCs could rely on cytokines and growth factors, such as platelet-derived growth factor, that mediate cell migration. In one study, intravenous administration of spinal fluid–derived MSCs was found to improve symptoms in patients following a stroke. However, numerous studies have raised doubt about whether the beneficial effects of MSCs in the treatment of neurological diseases are due to paracrine effects of these cells rather than their ability to directly lead to the regeneration of neuronal cells, which is required for functional recovery from neuronal diseases. For this reason, adult neural stem cells (NSCs), which exhibit both paracrine and direct differentiation effects, are also being pursued in the development of clinical therapies. The drawbacks with NSCs, however, are the difficulty of harvesting them from the unique microenvironment of the subventricular and subgranular zones in the brain and their less robust proliferation capacity. Despite the challenges, researchers have had success isolating very small brain samples for the isolation of NSCs. Although studies are in preclinical and early clinical trials, stem cell–based therapy seems to hold the greatest potential against diseases such as stroke, Parkinson's, and ALS. Unfortunately, this therapy may not hold great promise for patients with Alzheimer's because the widespread neuronal death in the brain makes harvesting cells for NSC difficult and the disease process that leads to neuronal cell destruction in the first place could quickly destroy transplanted cells.