The last decade has seen scientist progress from isolating pluripotent stem cells from early embryos and growing them in the laboratory to being able to generate them from terminally differentiated adult cells using viral insertion of key transcription factors. These remarkable advancements opened the doors, in theory, to a vast array of applications in cell therapy, gene therapy and disease modeling to treat and/or study numerous degenerative illnesses that had remained elusive until now. More specifically, these recent discoveries finally opened the door to potential cures to neurodegenerative disorders, such as ALS, Parkinson’s disease, Alzheimer’s disease, Huntington’s disease, or even Schizophrenia and Bipolar disorder, and even spinal cord injuries using neural stem cells therapies—by directly injecting them into the patient at specific locations for example. However, before I embark on the nature of neural stem cells and the current ongoing clinical trials to determine the extent of their applications, it might be wise to first remind ourselves of what we understand today to be a stem cell, or even what stemness means. Indeed, as our understanding of the biology and unique properties of stem cells grow, so must we refine the scope of what it is we are studying!
Our initial understanding of all stem cells is based on their functionality, as having three characteristics that set them apart from other cells: they are unspecified, they can divide and renew themselves for very long periods of time, and they can be induced, under certain conditions, to become differentiated cells with specialized functions. This definition seems simple and broad enough to encompass all stem cells you say? Well, not exactly. Indeed, this definition only works for embryonic or fetal stem cells that are only present for a short period in the lifetime of an organism. This definition can no longer be used when we try to separate transient progenitor cells from adult stem cells (or somatic stem cells). Efforts have thus been put in to refine this definition to adult stem cells that self-renew for the entire life span of an organism. However, this, also, wasn’t enough to take into account the different differentiating characteristics of adult stem cells: potency. Is a somatic stem cell that can only differentiate into one type of differentiated cell (unipotent) really a stem cell? Maybe a stem cell should be set apart based on its gene regulations, but again, this characteristic is not unique to stem cells. This makes you wonder about induced pluripotent stem cells doesn’t it? Are they really stem cells or simply pluripotent cells? Some scientists even define stemness as a system-level property as the environment has been shown to play a direct role in defining the nature of the stem cell (the niche makes the stem cell!). This subject is so complex that the majority of scientists decided to agree on a working definition for a stem cell, to be a clonal, self-renewing entity that is multipotent and thus can generate several differentiated cell types, while preserving numerical homeostasis—even though this definition is not applicable in all instances!
The origin of stem cells itself remains to be elucidated—not embryonic stem cells of course, which are derived from the inner cell mass of the blastocysts, but somatic stem cells. Everything gets complicated at the gastrulation event, after fertilization of the egg and the implantation of the zygote in the uterine wall. During gastrulation every cell in the embryo changes its position to become committed to one of the three germ layers, which themselves become properly positioned with respect to another within the context of the embryo. It is possible, thanks to numerous fate mapping studies, to determine what cells in various regions of the embryo will become. Remember that the three germ layers are the ectoderm, on the outside of the embryo, the endoderm, on the inside of the embryo and the mesoderm, in the middle, and that, after gastrulation, once a cell is committed to a germ layer, it will no longer form structures based on its location. Now, back to the origin of somatic stem cells dilemma; the common understanding is that development is achieved essentially through successive cell fate restrictions controlled by both intrinsic and extrinsic factors after gastrulation, and, thus, stem cells occur right after the formation of germ layers, restricted to their respective lineage by said germ layer. A second major theory implies that stem cells follow a similar developmental path as primordial germ cells, in that they avoid completely lineage commitment during gastrulation and migrate subsequently to specific tissues and organ niches. This matter remains to be elucidated and is actively researched by scientists all over the globe—it is an important matter and does imply determination of biomarkers of the different types of stem cells.
To get back to the subject at hand, and since we are not going to answer the question on the origin of somatic stem cells in this article, the common understanding on the development of neural stem cells (NSCs) is that it begins with the formation of nervous tissue from the ectoderm after gastrulation. It was observed that appearance of NSCs coincides with the induction of the neural plate and the appearance of restricted progenitor cells. It was also observed that developing and adult NSCs seem to acquire temporal and positional information, i.e. they give rise to region-appropriate progeny and earlier NSCs gives rise more frequently to neurons than glia compared to more mature NSCs. It is important to note that it was observed that NSCs for the most part do not give rise to all the neurons types in the adult brain. Indeed, they were found to be mostly limited to the production of GABA and glutamate neurons. The subject of NSCs is still relatively new, since they were first isolated in the early 1990s in the adult rodent striatum. Since then, many NSCs have been isolated from adult animals from a variety of locations in the central nervous system (CNS), including the spinal cord, the hippocampus, and the neocortex, as well as the striatum, and the search for NSCs’ new niches is still ongoing!
Despite having discovered so many endogenous NSCs in mammals, it was observed that their potential in “self-repair” after injury was not met because of, it is believed, constrains due to their environment, their restricted mobility and their limited numbers. Thus, the logical hypothesis followed: if NSCs were expanded ex vivo and implanted into regions needing repair, overcoming the in vivo limitations, the true potential of NSCs would be unlocked. Extensive research and experimentations were conducted based on this assumption, and are still conducted today with astonishing results and even more surprising discoveries about the properties of NSCs. For example, it was observed that exogenous NSCs are capable of sensing, homing in on, and responding adequately to neurogenic signals produced during degenerative processes in order to resume development. Additionally, it was observed that NSCs not only differentiate very efficiently into neural cells but also evade most of the obstacles that must be overcome by other gene or cellular therapies, i.e. NSCs can cross the blood-brain barrier. NSCs seem to be the answer scientists have been waiting for to treat extensive neurodegenerative processes as was previously said, dementia conditions, as well as spinal contusion and cerebellar degeneration, and many more. What are we waiting for to get these therapies up and running you ask? Nothing; scientists have been working hard at them for years, ever since they discovered the different NSCs’ niches!
Just to cite the pioneer in the field, Neuralstem, using its patented technology for “isolation and expansion of human neural stem cells from each of the NSCs niche regions of the developing central nervous system in virtually unlimited numbers from a single donated tissue,” is currently in phase II to treat ALS after having successfully demonstrated the safety of its procedure on 18 patients in phase I—using its patented world’s first intraspinal surgical device for the delivery of neural stem cells. From what I was able to gather, there were observations in several of the patients of slowed progression of lower extremity weakness, and one patient may have even improved just from the first intervention! Neuralstem is also in phase I/II to treat ischemic stroke and spinal cord injury, and is in pre-clinical phase to treat glioblastoma, multiple sclerosis, optic neuritis, Alzheimer’s disease, traumatic brain injury, peripheral nerve injury, diabetic neuropathy, lysosomal disease, Parkinson’s disease, cerebral palsy, and ischemic spastic paraplegia! As you might have guessed, one of the major difficulties lies in getting the right NSCs to the site of repair in order to produce only the right kind of neural cell types. At least, that is until we find the sacred grail of NSCs: a multipotent NSC that can produce all the different kinds of neural cells at the right time and place…or maybe not. A very recent paper, published by researchers at the Stanford University School of Medicine on April 14th, inspired by Shinya Yamanaka’s Nobel prize winning work, shows successful transformation of skin cells directly into oligodendrocyte precursor cells (direct lineage reprogramming !), the cells that wrap nerve cells in the insulating myelin sheaths that help nerve signals propagate. Could Shinya Yamanaka’s work on human induced pluripotent stem cells have opened the way to tomorrow’s neural stem cell (and stem cell in general) therapies? Many seem to think so; what about you?