role of stem cells in CNS repair - Maha Hammady.pptx

role of stem cells in CNS repair-Maha Hammady.pptx

1. By/ Maha Hammady Hemdan MBBCh- MMSc - Faculty of Medicine, Alexandria University. 2015 Role of Stem Cells in CNS Repair

2. It has long been believed that the adult mammalian central nervous system (CNS) does not regenerate after injury. However, recent progress in stem cell biology has provided the hope that regeneration of the injured CNS might be achieved. CNS ‘regeneration’ includes regeneration of neuronal axons replenishment of lost neural cells 1 2 3 axons C ell body function recovery of neural functions.

3. Ne ural ste m cells (NSCs)?? are somatic stem cells present within the CNS that have both multilineage potency and self- renewal capacity. How to study them?? 2 1 identification of their selective marker molecules selective culture methods their identification and isolation techniques 3

4. Based on these methods, three strategies for regeneration are being explored: 1 activation of the endogenous regenerative capacity 2 cell replacement therapy 3 Exosomes

5. Activation of the endogenous regenerative capacity of the NSC 01

6. Activation of the endogenous regenerative capacity of the NSC 01 activation of the endogenous regenerative capacity, is tightly associated with a phenomenon called “adult neurogenesis” . There is increasing evidence that neuronal cells are continuously produced in the adult mammalian brain under physiologic conditions, in the so-called “ adult neurogenic regions”: Negredo PN, Yeo RW, Brunet A. Aging and rejuvenation of neural stem cells and their niches. Cell stem cell. 2020 Aug 6;27(2):202-23. DOI:  10.1016/j.stem.2020.07.002

7. Activation of the endogenous regenerative capacity of the NSC 01 A- adult neurogenic regions: 1- Subventricular Zone (SVZ) of the lateral ventricles: There are specific cell types in the SVZ that could be distinguished based on their morphology; they classified these cells as types A, B and C. T ype B They are subsets of slowly dividing glial fibrillary acidic protein-positive cells that act as stem cells These stem cells (type B cells) give rise to type C They arise from type B cells. They are rapidly proliferating precursor cells . They also called transit-amplifying cells . They arise from type C cells. They are also called migrating neuroblasts . Newly generated neuroblasts migrate to olfactory bulb. T ype C T ype A

8. Activation of the endogenous regenerative capacity of the NSC 01 A- adult neurogenic regions: 1- Subventricular Zone (SVZ) of the lateral ventricles: There are specific cell types in the SVZ that could be distinguished based on their morphology; they classified these cells as types A, B and C. T ype B T ype C T ype A Okano H, Sawamoto K. Neural stem cells: involvement in adult neurogenesis and CNS repair. Philosophical Transactions of the Royal Society B: Biological Sciences. 2008 Jun 27;363(1500):2111-22. http://doi.org/10.1098/rstb.2008.2264

9. 4 3 2 1 Activation of the endogenous regenerative capacity of the NSC 01 A- adult neurogenic regions: 2- Hippocampal Dentate Gyrus: The hippocampus is a complex brain structure embedded deep into the temporal lobe. It plays a critical role in learning and memory. The hippocampus is divided into two parts: the dentate gyrus: formed of molecular, granular, and sub-granular zones. cornu ammonis (hippocampus proper): divided into CA1, CA2, CA3, and CA4 (also called the hilus) Both parts are separated by the hippocampal sulcus and curve into each other. Standring S. Gray'sanatomy : The anatomical basis of clinical practice. 42th ed. Philadelphia: Elsevier; 2020

10. A B C D Activation of the endogenous regenerative capacity of the NSC 01 A- adult neurogenic regions: 2- Hippocampal Dentate Gyrus: D A B C A B C D Tanaka T, Masubuchi Y, Okada R, Nakajima K, Nakamura K, Masuda S, Nakahara J, Maronpot RR, Yoshida T, Koyanagi M, Hayashi SM. Ameliorating effect of postweaning exposure to antioxidant on disruption of hippocampal neurogenesis induced by developmental hypothyroidism in rats. The Journal of Toxicological Sciences. 2019;44(5):357-72. Kino, Tomoshige . (2015). Stress, Glucocorticoid Hormones and Hippocampal Neural Progenitor Cells: Implications to Mood Disorders. Frontiers in physiology. 6. 230. 10.3389/fphys.2015.00230.

11. Activation of the endogenous regenerative capacity of the NSC 01 A- adult neurogenic regions: 2- Hippocampal Dentate Gyrus: V ascular niche Adult neurogenesis occurs within a ‘vascular niche’ in the SGZ, their endothelial cells released soluble factors that stimulated the self-renewal of NSCs , Astrocytic niche astrocytes in SVG supply local environmental factors that regulate neurogenesis

12. Activation of the endogenous regenerative capacity of the NSC 01 B- insult-induced neurogenesis : despite the presence of endogenous NSCs, most parts of the adult mammalian CNS are non- neurogenic under physiologic conditions . recent studies have shown that some insults, including ischemia, can induce neurogenesis in these non-neurogenic regions , is called “ insult-induced neurogenesis ” , indicating that some regenerative capacity is preserved (but very low) in the adult mammalian brain

13. Activation of the endogenous regenerative capacity of the NSC 01 B- insult-induced neurogenesis : The potential problems associated with insult-induced neurogenesis as a therapeutic target are the following: insult- induced neurogenesis is not always detectable. Its efficiency is low the newly generated neurons in response to CNS insult are mostly short-lived in most cases, insult- induced neurogenesis is not sufficient for functional recovery of the neural deficits caused by the insults,

14. Activation of the endogenous regenerative capacity of the NSC 01 B- insult-induced neurogenesis : Insult-induced neurogenesis follows a specific sequence of events, which are closely related to the normal process of CNS development and to the activities associated with the adult neurogenic sites. These are the steps: ( i ) Activation of adult NSCs: Various cellular stresses, including irradiation, oxidative stress, ischemia, and anti-cancer drugs, can induce these quiescent stem cells to enter the cell cycle and proliferate. (ii) Proliferation of transit-amplifying cells and migration of neuroblasts: SVZ-derived neuroblasts migrate towards the infarcted region in chain-like structures that run parallel to blood vessels . blood vessels in the damaged striatum play a crucial role in the migration and/or survival of these neuroblasts, by acting as a physical scaffold for migration and by releasing diffusible factors, such as brain-derived neurotrophic factor (BDNF).  (iii) the survival and maturation of the newborn neurons: Studies have indicated that approximately half of the  newborn  neurons die before reaching maturity in the hippocampal dentate gyrus and olfactory bulb, but the mechanisms regulating the apoptosis of these neurons are largely unknown.

15. Cell replacement therapy 02

16. Cell replacement therapy 02 The rationales for cell transplantation therapy are to replace cells that are lost due to injury with graft-derived cells . In recent studies, tissue- or embryonic stem cell-derived neural stem/precursor cells were transplanted and led to cell replacement and functional recovery. A wide range of stem cells are currently under investigation as potential alternative cell sources for neural transplantation: 1-Embryonic stem cells 2-Embryonic germ stem cells 3-Nuronal stem cells (NSCs) 4- Mesenchymal stem cells (MSCs)

17. Cell replacement therapy 02 cell sources for neural transplantation: 1-Embryonic stem cells: embryonic stem cells, are derived from the inner cell mass of blastocysts donated following in vitro fertilization. They are pluripotent ; able to differentiate into cells from all three germ layers. Embryonic stem cells can be expanded in vitro for prolonged periods of time without loss of pluripotency. ethical concerns Sciorio R, El Hajj N. Epigenetic risks of medically assisted reproduction. Journal of Clinical Medicine. 2022 Apr 12;11(8):2151.

18. Cell replacement therapy 02 cell sources for neural transplantation: 2-Embryonic germ stem cells : Embryonic germ stem cells primordial germ cells  Godoy, Naira & Martins, Daniele & Souza, Aline. (2021). Step by Step about Germ Cells Development in Canine. Animals. 11. 598. 10.3390/ani11030598. They are derived from the gonads of the developing fetus. they share many of the properties of human embryonic stem cells in their potency. Their derivation is considerably easier than that of human embryonic stem cells, both in terms of the success rate of conversion of starting material into a rapidly proliferating, pluripotent cell line and in terms of the availability of source material. ethical concerns

19. Cell replacement therapy 02 cell sources for neural transplantation: 3-Nuronal stem cells (NSCs): An alternative potential source of neurons for brain repair is to harvest stem-like progenitor cells directly from either the fetal or adult brain. Such NSCs are “ neurally ” specified, meaning that there is no need to receive the developmental signals responsible for initial early direction of the cells towards a neural lineage. fetal NSCs can be expanded in vitro for 6 months Adult NSCs show similar properties in vitro and could potentially be used for autologous transplantation; however, their expansion potential is even more limited than that of fetal NSCs. The effectiveness of both fetal and adult NSCs when transplanted into in vivo models remains poor . ethical concerns Olynik , Brendan & Rastegar , Mojgan . (2012). The Genetic and Epigenetic Journey of Embryonic Stem Cells into Mature Neural Cells. Frontiers in Genetics. 3. 81. 10.3389/fgene.2012.00081.

20. Cell replacement therapy 02 MSCs may represent somatic stem cell source for neural transplantation therapy. They lack ethical controversy They provide autologous transplants, thus avoiding any risk of rejection. These cells can be derived from various tissues and thus exhibit slightly differing final properties cell sources for neural transplantation: 4- Mesenchymal stem cells (MSCs) Andrzejewska , S. Dabrowska , B. Lukomska , M. Janowski , Mesenchymal Stem Cells for Neurological Disorders. Adv. Sci. 2021, 8, 2002944. https://doi.org/10.1002/advs.202002944

21. Cell replacement therapy 02 Disease application: A-Neurodegenerative diseases : 1-Parkinson’s disease (PD): PD it is a progressive neurodegenerative disease, in which dopaminergic neurons in the substantia nigra selectively degenerate. Motor symptoms generally do not develop until 75% of the dopaminergic neurons have been lost. A variety of drugs, including dopamine agonists or L-DOPA, are effective in providing symptomatic treatment early in the course of the disease. However, they only remain effective for a limited period in most patients . Studies have provided the proof that cell replacement therapy is a viable strategy for the treatment of neurodegenerative disease. Moreover, the locally regulated dopamine release by transplanted cells at synaptic targets improves at least some of the most debilitating symptoms in both animals and patients. https://www.neurolab360.com/blog/progression-of-parkinsons-disease

22. Cell replacement therapy 02 Disease application: A-Neurodegenerative diseases : 2-Huntington’s disease (HD): HD affects the basal ganglia. It is caused by an autosomal dominant mutation in the  huntingtin  gene causing loss of a subset of forebrain GABAergic neurons , with the emergence of a variety of motor symptoms at present, no disease modifying treatments are available for this progressive fatal neurodegenerative disease. Clinical trials using transplantation of primary fetal stem cells into HD are in the early stages but it is becoming clear that at least some patients are experiencing an improvement or stabilization of a number of symptoms for a period of several years. Because these studies are at an early stage, many unresolved issues remain, e.g. the determination of the clinical stage at which transplantation is most effective and the optimum cell number to graft. Further clinical studies will be required to address these problems.

23. Cell replacement therapy 02 Disease application: A-Neurodegenerative diseases : 3-Amyotrophic lateral sclerosis (ALS) https://www.theborneopost.com/2018/03/14/als-the-disease-that-stephen-hawking-defied-for-decades/ ALS is another chronic neurodegenerative disease in which motor neurons in the ventral grey matter of the spinal cord undergo degeneration leading to progressive paralysis and death over several years. This presents a more difficult challenge in terms of cell replacement therapy: regarding the way to achieve an adequately distributed cell replacement the extent of axon regeneration required of motor neurons to reinnervate distal muscle targets. ALS is a more rapidly progressing disease than HD and PD

24. Cell replacement therapy 02 Disease application: A-Neurodegenerative diseases : 4-Alzheimer’s disease (AD) AD is the most common form of dementia. The primary post-mortem diagnostic criteria is the pathological appearance of senile plaques and neurofibrillary tangles ( abnormal accumulations of a protein called tau that collect inside neurons ) with early predominance in temporal, and parietal lobes and in subcortical hippocampal and other limbic circuits. However, in the early stages, the disease has been argued to affect the cholinergic forebrain neurons relatively discretely, raising the possibility of targeted cholinergic cell replacement as a possible reparative strategy. Austin C. Boese, Milton H. Hamblin, Jean- Pyo Lee, Neural stem cell therapy for neurovascular injury in Alzheimer's disease, Experimental Neurology, Volume 324, 2020, 113112, ISSN 0014-4886, https://doi.org/10.1016/j.expneurol.2019.113112 .

25. Cell replacement therapy 02 Disease application: B-Trauma/injury : 1-Ischaemia: Ischemia involves the restriction of blood flow, and thus oxygenation, to selected brain leading to degeneration of neurons in that area over the following few days. Depending on the nature ,extent and position of the interruption of blood flow, a wide range of different types of neurons , as well as glia . These factors make it difficult to design stem cell therapies with the aim of specifically replacing neurons in the damaged circuits. although patients with stroke lesions in particular areas , such as the striatum , could potentially benefit from progress made for specific diseases such as HD in the future . However, neuroprotective strategies with stem cells may be of benefit for patients if given early enough. Netter FH. Atlas of human anatomy, Professional Edition E-Book: including NetterReference . com Access with full downloadable image Bank. Elsevier health sciences; 2014 May 20.

26. Cell replacement therapy 02 Disease application: B-Trauma/injury : 2-Spinal cord injury: Spinal cord injury presents a different challenge for cellular repair strategies because it consists primarily of an acute severance of long spinal axons . The problem arises from the lack of significant re-growth of the proximal axon; this may at least partly be caused by inhibitory signals from the myelinated environment and the glial scar formed around areas of injury. One repair strategy is to introduce cells, such as Schwann cells , which support re-growth of peripheral nerves, into the site of injury with the aim of providing a more permissive substrate for axon outgrowth. In several of these models, However, the anatomical sprouting in these cases is typically limited , extending mostly to only several millimeters . Ren, Zhiwu , Wang, Yu, Peng, Jiang, Zhao, Qing and Lu, Shibi . "Role of stem cells in the regeneration and repair of peripheral nerves" Reviews in the Neurosciences, vol. 23, no. 2, 2012, pp. 135-143.  https://doi.org/10.1515/revneuro-2011-0069

27. Cell replacement therapy 02 Disease application: C-Demyelinating disease : Multiple sclerosis (MS): MS is an autoinflammatory disease characterized by repeated focal inflammatory reactions that lead to local loss of myelinating glial cells . F ollowed by re-myelination and functional recovery of the affected circuits but, with disease progression, re-myelination becomes less effective and the de-myelinated axons themselves begin to degenerate. Endogenous remyelination in the CNS is provided by oligodendrocyte progenitor cells (OPCs); a population of transit amplifying cells derived from stem cells of the SVZ are recruited from the vicinity of lesions to proliferate, differentiate and re-myelinate axons. The finding that repair by stem-like progenitor cells occurs naturally, makes stem cell transplantation an attractive option. the transplanted cells would simply mimic endogenous precursor differentiation. https://www.mayoclinic.org/diseases-conditions/multiple-sclerosis/multimedia/myelin-damage-and-the-nervous-system-illustration/img-20132116#:~:text=In%20multiple%20sclerosis%2C%20the%20protective,in%20parts%20of%20the%20body.

28. Regeneration of the damaged CNS is becoming feasible from the clinical aspect, although it remains primitive. Based on the above-mentioned facts, it is obvious that both ( i ) activation of the endogenous regenerative capacity and (ii) cell transplantation therapy are very important strategies for CNS repair. Elucidation of the cellular mechanisms of the stem cell regulation and normal CNS developmental process in combination with molecular-targeted drug discovery would be essential for the future development of innovative therapeutic interventions of various CNS damages including spinal cord injury, stroke, and neurodegenerative disorders.

29. Exosomes 3

30. Exosomes 03 E xosomes are the smallest extracellular vesicles group with the nanoscale size of 40–150 nm. Exosomes bud directly from plasma membrane. Exosomes are the product of the fusion of multivesicular bodies (MVB) with the plasma membrane. They are secreted by various cells , also some cells produce more exosomes than other cells. Structurally, exosomes are composed of a phospholipid bilayer and cytosolic contents which are representative of its donor cells. Exosomes are key tools for transmitting paracrine signaling to other cells. They can cross the blood brain barrier (BBB) Discovering such abilities of exosomes in addition to weak stimulation of the immune system, crossing of the BBB, and long-term stability in the circulation system enhanced their potential in creating new treatment strategies for a variety of diseases specially in the central nervous system (CNS) regenerative medicine field. Fayazi , N., Sheykhhasan , M., Soleimani Asl, S. et al. Stem Cell-Derived Exosomes: a New Strategy of Neurodegenerative Disease Treatment. Mol Neurobiol 58, 3494–3514 (2021). https://doi.org/10.1007/s12035-021-02324-x

31. Andrzejewska , S. Dabrowska , B. Lukomska , M. Janowski , Mesenchymal Stem Cells for Neurological Disorders. Adv. Sci. 2021, 8, 2002944. https://doi.org/10.1002/advs.202002944 Fayazi , N., Sheykhhasan , M., Soleimani Asl, S. et al. Stem Cell-Derived Exosomes: a New Strategy of Neurodegenerative Disease Treatment. Mol Neurobiol 58, 3494–3514 (2021). https://doi.org/10.1007/s12035-021-02324-x Negredo PN, Yeo RW, Brunet A. Aging and rejuvenation of neural stem cells and their niches. Cell stem cell. 2020 Aug 6;27(2):202-23. DOI:  10.1016/j.stem.2020.07.002 Hopf , Alois, Dirk J. Schaefer, Daniel F. Kalbermatten , Raphael Guzman, and Srinivas Madduri . 2020. "Schwann Cell-Like Cells: Origin and Usability for Repair and Regeneration of the Peripheral and Central Nervous System"  Cells  9, no. 9: 1990. https://doi.org/10.3390/cells9091990 Raghavendra  Upadhya ,  Leelavathi N. Madhu,  Sahithi   Attaluri , Daniel Leite Góes   Gitaí , Marisa R Pinson,  Maheedhar  Kodali, Geetha Shetty, Gabriele  Zanirati ,  Smrithi  Kumar, Bing Shuai, Susan T Weintraub & Ashok K. Shetty (2020) Extracellular vesicles from human iPSC-derived neural stem cells: miRNA and protein signatures, and anti-inflammatory and neurogenic properties, Journal of Extracellular Vesicles, 9:1, DOI:  10.1080/20013078.2020.1809064 Picard- Riera , N., Nait-Oumesmar , B. and Baron-Van Evercooren , A. (2004), Endogenous adult neural stem cells: Limits and potential to repair the injured central nervous system. J. Neurosci . Res., 76: 223-231.  https://doi.org/10.1002/jnr.20040

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34. Tanaka T, Masubuchi Y, Okada R, Nakajima K, Nakamura K, Masuda S, Nakahara J, Maronpot RR, Yoshida T,Koyanagi M, Hayashi SM. Ameliorating effect of postweaning exposure to antioxidant on disruption of hippocampal neurogenesis induced by developmental hypothyroidism in rats. The Journal of Toxicological Sciences. 2019;44(5):357-72. Netter FH. Atlas of human anatomy, Professional Edition E-Book: including NetterReference . com Access with full downloadable image Bank. Elsevier health sciences; 2014 May 20. Sciorio R, El Hajj N. Epigenetic risks of medically assisted reproduction. Journal of Clinical Medicine. 2022 Apr 12;11(8):2151. Mandel SA, Morelli M, Halperin I, Korczyn AD. Biomarkers for prediction and targeted prevention of Alzheimer's and Parkinson's diseases: evaluation of drug clinical efficacy. EPMA J. 2010 Jun;1(2):273-92. doi : 10.1007/s13167-010-0036-z. Anand KS, Dhikav V. Hippocampus in health and disease: An overview. Annals of Indian Academy of Neurology. 2012 Oct 1;15(4):239-46. https://doi.org/10.4103%2F0972-2327.104323 https://www.neurolab360.com/blog/progression-of-parkinsons-disease R. L. Isaacson,Encyclopedia of Neuroscience, edited by L. R. Squire, Academic Press 2004. https://doi.org/10.1016/B978-008045046-9.02026-X https://www.theborneopost.com/2018/03/14/als-the-disease-that-stephen-hawking-defied-for-decades/

35. Godoy, Naira & Martins, Daniele & Souza, Aline. (2021). Step by Step about Germ Cells Development in Canine. Animals. 11. 598. 10.3390/ani11030598. Olynik , Brendan & Rastegar , Mojgan . (2012). The Genetic and Epigenetic Journey of Embryonic Stem Cells into Mature Neural Cells. Frontiers in Genetics. 3. 81. 10.3389/fgene.2012.00081. Kino, Tomoshige . (2015). Stress, Glucocorticoid Hormones and Hippocampal Neural Progenitor Cells: Implications to Mood Disorders. Frontiers in physiology. 6. 230. 10.3389/fphys.2015.00230.

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