Stem Cells

differentiationA few weeks ago, a “Current Perspective of Stem Cell Therapy in Neurodegenerative and Metabolic Diseases” was published in the Molecular Neurobiology journal [1], New, exciting advances looking for a cure for neurodegenerative diseases by using stem cells, are summarized in that review.

A stem cell is one with the ability to continuously divide and differentiate into various other kinds of cells/tissues. Pluripotent embryonic stem cells (ES) may additionally maintain the pluripotent state over extended periods in culture and they may contribute to all three germ layers. Adult stem cells, on the other hand, are undifferentiated cells living among differentiated cells in a well-developed tissue or organ. They may renew itself and differentiate into another cell type of the tissue or organ. They are referred to as somatic cells (the opposite to germ, sperm cells or eggs). Unlike embryonic stem cells, which are defined by their origin the origin of adult stem cells in some mature tissues is still under investigation. it is an exciting investigative avenue since the differentiation of adult stem cells can be controlled in the laboratory.

Thus, by using tissue engineering techniques is feasible taking organ-specific cells for seeding a scaffold ex vivo (which means: experimentation or measurements done in or on tissue from an organism in an external environment with minimal alteration of natural conditions). Some three-dimensional highly porous biomaterials may act as templates or scaffolds for tissue regeneration. The cell-based (although not necessarily stem cell-based) is named ‘guided tissue regeneration’ in which a scaffold is designed to encourage regeneration solely by cells residing at the site of its transplantation. In such a manner that by transplanting human neural stem cells (hNSCs), is possible to treat stroke-related brain injuries. The grafts inside the tissue (parenchyma) have been shown provide structural support for the delivered cells. The bio-scaffold similar to the natural extracellular matrix (ECM)  allows to those human neural stem cells the creation of de novo tissue, which is possible to monitor by magnetic resonance imaging techniques [2].

figure-2-3d-brain-like-tissue-model-a-porous-silk-sponge-scaffold-b-livedead
3D brain-like tissue model. ( A ) Porous silk sponge scaffold. ( B ) Live/dead staining of neurons at day 1 upon seeding on silk scaffold before collagen embedding (green-live cells, red-dead cells). (Taken from Chwalek K, Sood D, Cantley WL, et al. Engineered 3D Silk-collagen-based Model of Polarized Neural Tissue.  JoVE. 2015(105):e52970.

The  Kumar’s “Current Perspective of Stem Cell Therapy in Neurodegenerative and Metabolic Diseases” embraces not only Alzheimer’s disease and Parkinson’s disease (PD), but also Huntington’s disease (HD), prion diseases, amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA), motor neuron diseases (MNDs), and spinocerebellar ataxia (SCA) along with metabolic and toxic diseases, which happen as an aftereffect of neurodegenerative diseases.

In Alzheimer’s, two approaches have been developed: 1) to activate and recruit from inside (endogenous) stem cells (SCs) to the repair site, and, 2) to transplant SCs and replacing the damaged cells. In the first case, endogenous SCs can be stimulated by powerful signaling molecules known as cytokines, which is followed by formation of new neurons (neurogenesis) with the improvement in learning and memory. In this manner, hematopoietic cells of bone marrow origin can be mobilized into the brain for enhancing the learning and memory as observed in AD model mice. In the second case, SCs derived from various sources, such as bone marrow, umbilical cord blood, and endothelial cells, when transplanted into the brain of the AD animal models have immense potential to neutralize neurodegenerative progression.

In animal models, neural precursor cells can be intravenously administered and then appear in brain damaged areas while is discussed if they are able to induce functional recovery. Transplanted stem cells or neural precursor cells are able to survive, then migrating, and finally they may differentiate into cholinergic neurons, and other brain cell components such as astrocytes, and oligodendrocytes with a chance to ameliorate the learning/memory deficits. In addition to replacing lost or damaged cells, stem cells may stimulate endogenous neural precursors, or enhance neuroplasticity. Even they downregulate neuronal programmed cell death, or apoptosis, a kind of cell suicide which play a key role in the mechanisms leading to neurodegeneration. (CNS Neurol Disord Drug Targets. 2011 Jun;10(4):459-85)

who-could-be
Neural precursor cells promote behavioral restoration in a mouse model in which the acetylcholine producer cells are degenerated [acetylcholine is a neurotransmitter, a messenger, particularly deficient in Alzheimer’s brain]. Also, the transplantation of human neural stem cells genetically manipulated to over-expressing choline acetyltransferase (the enzyme in charge of synthesizing acetylcholine) into chemically damaged rat brains, were able to improve memory and learning ability in these animals [3].

In humans, a review of recent clinical trials (JAD. 2016; 54(3):879-89)[3] reveals a some quite different story.

Human umbilical cord blood-derived Mesenchymal Stem Cells (hUCB-MSCs), a kind of multipotent stem cells,  have been injected into the human brain, into the hippocampus, specifically; by taking into account that the hippocampus, is the earliest affected zone in Alzheimer’s brain. 12 weeks after, and 24 months after the injection, human subjects with AD were meticulously evaluated by using brain computerized tomography (CT), MRI, fludeoxyglucose positron emission tomography (FDG-PET), Pittsburgh compound B PET (PIB-PET), blood samples, a neuropsychological test battery, and clinical evaluation. The results: there were not side effects, but not a significant clinical efficacy either (Clinicaltrials.gov, NCT01297218, NCT01696591)[4]

According to “Stem Cell Therapy for Alzheimer’s Disease: A Review of Recent Clinical Trials. Journal of Alzheimer’s disease”, published in 2016, there are six stem cell clinical trials in patients with Alzheimer’s disease. They are formally registered in Clinicaltrials.gov, from the National Institute of Health with the numbers: NCT01297218, NCT01696591, NCT2054208, NCT01547689, NCT02672306, and NCT02600130. Some of them -initiated 5 or 6 years ago- must be “complete” studies, some others are “in progress”, but no one has uploaded their results yet, as we checked by revisiting the official clinicaltrials.gov web page.

This take us to another paper published in 2013 and entitled, with suspicion, “Stem Cell Therapy for Alzheimer’s Disease: Hype or Hope?”, which concludes: “most of the current research is hype as there were safety (e.g. Embryonic stem cells induced tumorigenesis) and ethical issues involved in the use of fetal stem cells. Also, there is not a single animal model which could simulate the full aspect of AD. Nevertheless, there is still hope—the use of MSCs is free from ethical problems and could potentially be a type of immunomodulatory treatment for AD. Also, with the advancement in the use of iPSC, hopefully, we could model the disease better and eventually translate stem cell research into human studies with the aim to finally solve the enigma of restoring the memory.” [5]

… Will continue soon

[1] Kumar A, Narayanan K, Chaudhary RK, et al. Current Perspective of Stem Cell Therapy in Neurodegenerative and Metabolic Diseases. Molecular neurobiology. 2016.

[2] Bible E, Dell’Acqua F, Solanky B, et al. Non-invasive imaging of transplanted human neural stem cells and ECM scaffold remodeling in the stroke-damaged rat brain by (19)F- and diffusion-MRI. Biomaterials. 2012; 33(10):2858-71.

[3] Kang JM, Yeon BK, Cho SJ, et al. Stem Cell Therapy for Alzheimer’s Disease: A Review of Recent Clinical Trials. Journal of Alzheimer’s disease : JAD. 2016; 54(3):879-89.

[4] Kim HJ, et. al., (2015) Stereotactic brain injection of human umbilical cord blood mesenchymal stem cells in patients with Alzheimer’s disease dementia: A phase 1 clinical trial. Alzheimers Dement (N Y) 1, 95-102.

[5] Liu AKL. Stem cell therapy for Alzheimer’s disease: hype or hope? Bioscience Horizons: The International Journal of Student Research. 2013; 6:hzt011-hzt.

 

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