Regenerative Medicine for Neurological Diseases 2024 Fall PDF

Regenerative Biology and Disease Regenerative Medicine for Neurological Diseases Dr. Vijendra Sharma University of Windsor – Department of Biomedical Sciences Human Stem Cells in Regenerative Medicine The major types of stem cells are 1. Embryonic and indu...

Regenerative Biology and Disease Regenerative Medicine for Neurological Diseases Dr. Vijendra Sharma University of Windsor – Department of Biomedical Sciences Human Stem Cells in Regenerative Medicine The major types of stem cells are 1. Embryonic and induced pluripotent stem cells differentiate into all of the cells of adult mammals 2. Skeletal stem cells or mesenchymal stromal cells (MSCs) differentiate more selectively into osteoblasts, chondrocytes, myocytes and adipocytes 3. Somatic or non-embryonic adult stem cells found in only one organ system where they yield the specialized cells of those tissues Edward J. Goetzl et al 2024 Regulation of stem cell state by niche factors Quiescent stem cells are − Smaller in size, − lower RNA and protein content − less mitochondria Stem Cell Quiescence − Is controlled and maintained by elevated niche factors such as  collagen V,  calcitonin  thrombopoietin Edward J. Goetzl et al 2024 Regulation of stem cell state by niche factors. Delta-like canonical Notch ligand 1 (DLL1) stimulate Notch Delta like canonical Notch Intracellular Domain (NICD) and ligand 1 RBPJ DNA-binding transcription factor signal stem cell quiescence and self-renewal. p21 inhibits cyclin-dependent kinase 4/6 activation of E2F transcription factor enhancement of cell cycle progression from G1 Dashed to S. arrow indicates generation or Edward J. Goetzl stimulation et al 2024 Regulation of stem cell state by niche factors ERK and p38 are protein kinases that transmit mitogenic signals to activate gene expression. The PI3K-AKT pathway stimulates cell growth, metabolism and protein synthesis to promote G1 to S transition and cell cycle entry. CXCL12 chemokine or SDF-1 type 1 stromal cell-derived factor evokes migration of NSCs Bone morphogenetic protein (BMP) and retinoic acid (RA) induces differentiation of NSCs. Edward J. Goetzl et al 2024 Alzheimer's Disease: Neurobiology Alzheimer’s disease (AD) is a degenerative brain disease and the most common type of dementia. Characterized by a decline in memory, language, problem-solving and other cognitive skills. This decline occurs because of the loss of neurons (particularly pyramidal cells) in regions of the brain involved in cognitive function. People in the final stages of the disease are bed-bound and require around-the-clock care. Alzheimer’s Disease Neuropathology LEFT is a normal healthy brain and on the RIGHT is a brain with advanced Alzheimer's disease The AD brain exhibits extreme shrinkage of the neocortex, severely enlarged ventricles and shrinkage of the hippocampus (a region that plays a critical role in memory). This atrophy reflects the loss of vulnerable neurons, principally pyramidal, cholinergic, noradrenergic and serotonergic neurons. Hallmarks of Alzheimer’s Disease Two key hallmarks of AD are the formation of 1. Dystrophic neurites around a central core of amyloid (plaques). 2. Abnormal filaments (neurofibrillary tangles) made up of a highly phosphorylated form of the microtubule- associated protein tau in neurons. Normal Memory Processing Short-term (or working memory) allows recall for a period of several seconds to a minute without rehearsal. long-term memory can store much larger quantities of information for a period that can be as long as a lifetime.  explicit (conscious) and  semantic (facts and general knowledge)  episodic (personally experienced events).  entorhinal cortex and hippocampus.  implicit (unconscious) memory.  Classical conditioning, priming memory. (enhanced identification of objects or words)  Procedural memory (cognitive and motor skills) Both episodic and semantic memory are affected early in the course of AD. As the disease progresses these deficits become progressively worse and are accompanied by impairments in implicit (unconscious)conceptual memory. Memory storage as a psychological process 1. Memories have different life spans Short-lived memories (short-term memory; STM) Long-lived memories (long-term memories; LTM) are stable for days to months to years. 2. Repetition makes the memory last longer Hermann Ebbinghaus (1850-1909)  Two memory systems: STM and LTM 1957 – McGill University (Canada) - Scoville and Milner HM (1926-2008) Scoville and Milner, 1957, J Neurol Neurosurg Psychiatry Normal Memory Processing Progression of Alzheimer’s Disease Currently, a definitive diagnosis of AD can only be made on the basis of a postmortem examination of the brain. The disease begins about 15 years before symptoms appear and starts to emerge in a prodromal form (amnesic mild cognitive impairment). The entorhinal cortex is affected first, Leading to impairments in episodic memory. Disease spreading to other areas of the neocortex, additional domains of cognitive function become impaired and the syndrome of dementia becomes evident. Brain structures affected in Alzheimer’s Disease The entorhinal cortex is affected first. Leading to impairments in episodic memory. Disease spreading to other areas of the neocortex, additional domains of cognitive function become impaired, and the dementia becomes evident. Dysregulated translation through phosphorylation of eukaryotic initiation factor- 2α (eIF2α) contribute to Alzheimer's disease (AD) and related memory impairments 20x 40x Amounts of phosphorylated eIF2α are significantly elevated in sporadic AD brains Tao Ma (2013), Nature Neuroscience Adult neurogenic development is distinctly affected by neuropsychiatric disease. Adult hippocampal neurogenesis is characterized by the development and maturation of stem cells into granular cell layer neurons in the dentate gyrus. Conditions that impair the adult neurogenic process include:  chronic drug/alcohol  major depression and related disorders  Schizophrenia Psychosocial stress, induce apoptotic damage (i.e., red circles within cells, indicative of cellular breakdown) and subsequently limit the number of radial glia-like stem cells, multipotent progenitors, immature neurons, and mature granule cells in the hippocampal dentate gyrus. Several conditions increase or reverse the ability of biological processes to elevate the development and maturation state of adult neurons in the hippocampus. Lee Peyton et al. 2021 Mesenchymal stem cell therapy for neurological diseases Mesenchymal stem/stromal cells (MSCs) can be isolated from several adult and perinatal tissues, including bone marrow, umbilical cord, and adipose tissue. MSC neuroprotective actions through secretion of cytokines, trophic factors, and microRNAs, among other molecules, which are released directly into the extracellular space or packaged in micro vesicles and exosomes. MSC efficacy can be improved in vitro prior to transplantation, by different preconditioning methods and/or genetic engineering to increase the production or release of specific factors. Cell therapy restore microglial Trem2 function in Alzheimer's Genome-wide association studies in sporadic, late-onset AD have identified many variants in microglial genes enriched in patients, including the variant TREM2-R47H, which is among the strongest genetic risk factors for the disease. loss of function of TREM2 results in Nasu- Hakola disease characterized by an early-onset neurodegeneration of frontotemporal dementia. TREM2 function can be restored by replacing mutant microglia throughout the brain with circulation-derived myeloid cells (CDMCs) following hematopoietic cell transplantation in a mouse model of AD. Yongjin Yoo et al 2023 Clinical trials using mesenchymal stem/stromal cells in amyotrophic lateral sclerosis Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS) Milena B. P. Soares ei al. 2022 Normal Memory Processing Short-term (or working memory) allows recall for a period of several seconds to a minute without rehearsal. long-term memory can store much larger quantities of information for a period that can be as long as a lifetime.  explicit (conscious) and  semantic (facts and general knowledge)  episodic (personally experienced events).  entorhinal cortex and hippocampus.  implicit (unconscious) memory.  Classical conditioning, priming memory. (enhanced identification of objects or words)  Procedural memory (cognitive and motor skills) Both episodic and semantic memory are affected early in the course of AD. As the disease progresses these deficits become progressively worse and are accompanied by impairments in implicit (unconscious)conceptual memory. tem Cell-Based Therapies for Parkinson Disease Parkinson’s Disease (PD) is the second most common neurodegenerative disease after Alzheimer’s Disease. Diagnosis is primarily clinical and is based on the presence of asymmetric or unilateral resting tremor, bradykinesia and rigidity. Pathological hallmark of PD is the accumulation of α-synuclein in intraneuronal Lewy bodies and neurites. The known causes of PD include several different gene mutations of proteins including α-synuclein, LRRK2, parkin and PINK1 and glucocerebrosidase (GBA1). These motor features are predominantly the result of the degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc) and loss of striatal innervation. Neurodegeneration also develops in non-dopaminergic pathways and results in a series of non-motor features that include cognitive impairment, sleep disorders and autonomic dysfunction. The Anatomy of Parkinson's Disease PD affects nerve cells in Basal Ganglia and cause moment related loss of coordination. Idiopathic Parkinson’s: Idiopathic means the cause is unknown. Vascular parkinsonism: This condition tends to cause early balance and walking problems. Drug-induced parkinsonism: People with this tend to have parkinsonism-type symptoms equally on both sides of their body. Toxin-induced parkinsonism: People with this have more severe "cogwheel rigidity," which is a jerky pattern to their movements (similar to the second hand of a clock). The Anatomy of Parkinson's Disease Approaches to stem cell-derived neural grafting in Parkinson’s disease Embryonic stem cells Induced pluripotent stem cells Other cell types  Mesenchymal stem cells can be derived from the bone marrow and have also been considered with regard to development of regenerative treatments in PD. No success in generating authentic midbrain dopaminergic neurons from mesenchymal stem cells Early clinical trial show promising results results https://aspenneuroscience.com/ Extensive graft-derived is maintained 24 years Extensive graft-derived dopaminergic innervation is maintained 24 years after transplantation in the degenerating parkinsonian brain Patient with Parkinson’s disease Putamen (in red) shown within the brain underwent unilateral cell transplantation in the putamen with human embryonic mesencephalic tissue. The patient enjoyed major clinical benefits for at least a decade after transplantation. Wen Li et al 2016, Survival of transplanted dopaminergic neurons in the three graft deposits. (A, B, and F) Wen Li et al 2016, MSC Therapy in Neurological Diseases Clinical trials using mesenchymal stem/stromal cells in amyotrophic lateral sclerosis. retinal diseases. Brain Stroke spinal cord injury. autism spectrum disorder. Alzheimer’s disease Parkinson’s disease Milena B. P. Soares ei al. 2022