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NEURAL STEM CELLS AND NEUROGENESIS

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Neural stem cells are multipotent cells capable of self-renewal and proliferation, leading to the formation of progenitor cells. Historical studies have traced the discovery of neurogenesis in various species, demonstrating the potential for brain cell regeneration, with ongoing debates about the persistence of neurogenesis in adults. Key markers such as nestin and sox2 play crucial roles in maintaining neural stem cell identity and function.

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NEURAL STEM CELLS AND NEUROGENESIS
WHAT ARE NEURAL STEM CELLS? Multipotent cells with the ability to self-renew and proliferate in order to give rise to progenycells
NEURAL STEM CELLS AND NEUROGENESIS
HISTORY OF NEURAL STEM CELLS THE NEURON DOCTRINE – each neuron is an individual entity that forms the basic unit of neural circuitry. This was presented by Santiago Ramón y Cajal in 1894. “Intheadult…thenervepathsaresomething fixed,ended,and immutable.Everythingmay die,nothingmayberegenerated.” The first evidence of adult brain neurogenesis came from JOSEPH ALTMAN in the 1960s from his studies in rats.
INITIAL WORK ISOLATION Initial works in 1958 (Messier and Leblond) and 1961 (Smart) employed the use of tritiated thymidine for labeling brain cells of mice  radioactivity in the subventricular zone (SVZ) of the brain, the hippocampus, cerebral cortex and fornix . In 1989, DR SALLY TEMPLE was able to isolate neural stem cells from rodent brain and culture them in vitro.
THE ROAD MAP – HISTORICAL PERSPECTIVE EXPERIMENT BY YEAR FINDINGS LeBlond and Smart 1961 Tritiated thymidine labeling of cells- Discovered neuroglial cells in mouse brain Altman and Das 1965, 1967 Neurogenesis in adult brain of rats and guinea pigs, respectively Kaplan and Hinds 1977 Adult-born neurons in dentate gyrus and olfactory bulb coupling tritiated thymidine and electron microscopy Goldman and Nottebohm 1983 Neurogenesis in song birds (canaries) Rakic 1985 Neurogenesis in monkeys happened only in early age and not in adults Reynolds and Weiss 1992 Used certain growth factors Eriksson et al. 1998 Neurogenesis in adult human hippocampus in cancer patients Kornack and Rakic 1999 Re-examined neurogenesis in macaque monkey and confirmed neurogenesis in the DG Sorrells et al. 2018 Neurogenesis occurs only in the young, and not in adults Boldrini et al. 2018 Neurogenesis occurs in adults, including old individuals
ROSTRAL MIGRATORY STREAM Experiment by Altman in rats showed radially-oriented streaks of cells in apparent migration. They were most prominent around the rostra1 wall of the anterior horn of the lateral ventricle and connected the lateral and olfactory ventricles. This L-shaped structure, which first moves vertically and then horizontally, penetrates the laminated olfactory bulb and is known as Rostral Migratory Stream. Smart in his experiment had established that the subependymal layer extended in mice from the anterior wall of the lateral ventricle rostrally into the olfactory bulb. RMS
MARKERS Some researchers theorize that the SGZ is a conducive environment for the proliferation of NSCs into granule cells, from which they migrate to the granule cell layer. Quiescent radial glia-like type I neural progenitor cells (QNPs) Type II Intermediate neural progenitor cells (INPs) Type III Intermediate neural progenitor cells (INPs) Immature neurons Mature granule neurons that integrate into the hippocampal circuitry SOXBLBP 2, NESTIN, Ki67, NESTIN Lose expression of neural stem cell markers and gain expression of neuronal markers DCX, PSA-NCAM NeuN, β-III TUBB, CALBINDIN
MARKERS OF NEURAL STEM CELLS Exclusively found in vertebrates Belongs to the family of Intermediate Filament proteins Role : Self renewal of neural stem cells NESTIN Green Fluorescent Protein is an excellent marker of neural stem cells, so when the Nes/GFP screening was done, it was seen that the Nes –/– individuals had very low expression of GFP indicative of the fact that absence of Nestin caused neural stem cells to differentiate
SOX2  Transcription factor  Role: Important for maintenance of neural stem cells Sox2 helps in hippocampal development as well. When Sox2 was deleted in mice and postnatal observations were done. This was observed :
The defective hippocampal development was seen to mimic the mutation of Shh or of its receptor Smo. The absence of Shh causes an arrest of postnatal hippocampal development which closely resembles that of Sox2 knockout mouse, strongly suggesting that Sox2 controls hippocampal development via regulation of Shh.
β- CATENIN Role: Determines neural stem cell state Wnt signaling is a conserved cell signaling system that is thought to play multiple roles in NSC self- renewal, neurogenesis, embryonic patterning, and homeostatic tissue regeneration in the developing and adult brain. CELL PROLIFERATION CELL DIFFERENTIATION
OTHER NEURAL STEM CELL MARKERS GFAP – marks astrocytes NeuN, βIII-tubulin – mark neurons GalC – marks oligodendrocytes DIFFERENTIATION MARKERS Musashi-1, Musashi-2, Pax3, Pax6, Hes1, Hes5, CD133, CD15, Vimentin
CONTROVERSY Sorrells et al. found a sharp drop in neurogenesis as the human brain ages Boldrini et al. find persistent adult neurogenesis in humans into the eighth decade of life
SORRELLS Maps of Ki-67+ (green) cells in the DG from samples of individuals that were between 22 gestational weeks and 35 years of age; GCL in blue. Ki-67+SOX1+ and Ki- 67+SOX2+ cells (arrows) are distributed across the hilus and GCL and the number of double-positive cells decreases between 22 gestational weeks and 1 year of age.
DCX+PSA-NCAM+ cells in the DG from birth to the age of 77 showing that the number of young neurons declines in the human DG
BOLDRINI (A and B) Co-expression of Sox2 and nestin in QNPs. (E) GFAP+ cells with apical process (white arrow) nestin+ INP (yellow arrow). (F) Nestin/Ki-67+ INP.
(M) Sox2+ cell decline in anterior-mid DG with aging. (N and O) Nestin+ and Ki-67+ cells do not decline with older age in anterior, mid, or posterior DG.
(A) PSA-NCAM and DCX expression in an immature neuron between subgranular zone (SGZ) and granule cell layer (GCL), two PSA-NCAM+/DCX cells, and 4’,6- diamidino-2-phenylindole (DAPI)+ nuclei. (G–H) Stable DCX+ immature neurons, NeuN+ mature granule neurons
ISSUES RAISED Post Mortem Delay - PMD. Boldrini’s study sample size age group DCX as a marker? Sorrells used patients who had epilepsy Use of 10% formalin Gerd Kempermann
There have been studies conducted after this controversy as well (in 2019) that lean towards Boldrini’s conclusion that neurogenesis does persist through an older age in healthy individuals as well as in patients suffering from mild cognitive impairments (MCI) and Alzheimer’s Disease. Tobin et al. observe persistent hippocampal neurogenesis in aging brains with no cognitive impairments, mild cognitive impairments, and Alzheimer’s disease. Elena P. Moreno-Jiménez et al. observe persistence of adult hippocampal neurons during both physiological and pathological aging in humans
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NEURAL STEM CELLS AND NEUROGENESIS

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NEURAL STEM CELLS AND NEUROGENESIS

  • 2. WHAT ARE NEURAL STEM CELLS? Multipotent cells with the ability to self-renew and proliferate in order to give rise to progenycells
  • 4. HISTORY OF NEURAL STEM CELLS THE NEURON DOCTRINE – each neuron is an individual entity that forms the basic unit of neural circuitry. This was presented by Santiago Ramón y Cajal in 1894. “Intheadult…thenervepathsaresomething fixed,ended,and immutable.Everythingmay die,nothingmayberegenerated.” The first evidence of adult brain neurogenesis came from JOSEPH ALTMAN in the 1960s from his studies in rats.
  • 5. INITIAL WORK ISOLATION Initial works in 1958 (Messier and Leblond) and 1961 (Smart) employed the use of tritiated thymidine for labeling brain cells of mice  radioactivity in the subventricular zone (SVZ) of the brain, the hippocampus, cerebral cortex and fornix . In 1989, DR SALLY TEMPLE was able to isolate neural stem cells from rodent brain and culture them in vitro.
  • 6. THE ROAD MAP – HISTORICAL PERSPECTIVE EXPERIMENT BY YEAR FINDINGS LeBlond and Smart 1961 Tritiated thymidine labeling of cells- Discovered neuroglial cells in mouse brain Altman and Das 1965, 1967 Neurogenesis in adult brain of rats and guinea pigs, respectively Kaplan and Hinds 1977 Adult-born neurons in dentate gyrus and olfactory bulb coupling tritiated thymidine and electron microscopy Goldman and Nottebohm 1983 Neurogenesis in song birds (canaries) Rakic 1985 Neurogenesis in monkeys happened only in early age and not in adults Reynolds and Weiss 1992 Used certain growth factors Eriksson et al. 1998 Neurogenesis in adult human hippocampus in cancer patients Kornack and Rakic 1999 Re-examined neurogenesis in macaque monkey and confirmed neurogenesis in the DG Sorrells et al. 2018 Neurogenesis occurs only in the young, and not in adults Boldrini et al. 2018 Neurogenesis occurs in adults, including old individuals
  • 7. ROSTRAL MIGRATORY STREAM Experiment by Altman in rats showed radially-oriented streaks of cells in apparent migration. They were most prominent around the rostra1 wall of the anterior horn of the lateral ventricle and connected the lateral and olfactory ventricles. This L-shaped structure, which first moves vertically and then horizontally, penetrates the laminated olfactory bulb and is known as Rostral Migratory Stream. Smart in his experiment had established that the subependymal layer extended in mice from the anterior wall of the lateral ventricle rostrally into the olfactory bulb. RMS
  • 8. MARKERS Some researchers theorize that the SGZ is a conducive environment for the proliferation of NSCs into granule cells, from which they migrate to the granule cell layer. Quiescent radial glia-like type I neural progenitor cells (QNPs) Type II Intermediate neural progenitor cells (INPs) Type III Intermediate neural progenitor cells (INPs) Immature neurons Mature granule neurons that integrate into the hippocampal circuitry SOXBLBP 2, NESTIN, Ki67, NESTIN Lose expression of neural stem cell markers and gain expression of neuronal markers DCX, PSA-NCAM NeuN, β-III TUBB, CALBINDIN
  • 9. MARKERS OF NEURAL STEM CELLS Exclusively found in vertebrates Belongs to the family of Intermediate Filament proteins Role : Self renewal of neural stem cells NESTIN Green Fluorescent Protein is an excellent marker of neural stem cells, so when the Nes/GFP screening was done, it was seen that the Nes –/– individuals had very low expression of GFP indicative of the fact that absence of Nestin caused neural stem cells to differentiate
  • 10. SOX2  Transcription factor  Role: Important for maintenance of neural stem cells Sox2 helps in hippocampal development as well. When Sox2 was deleted in mice and postnatal observations were done. This was observed :
  • 11. The defective hippocampal development was seen to mimic the mutation of Shh or of its receptor Smo. The absence of Shh causes an arrest of postnatal hippocampal development which closely resembles that of Sox2 knockout mouse, strongly suggesting that Sox2 controls hippocampal development via regulation of Shh.
  • 12. β- CATENIN Role: Determines neural stem cell state Wnt signaling is a conserved cell signaling system that is thought to play multiple roles in NSC self- renewal, neurogenesis, embryonic patterning, and homeostatic tissue regeneration in the developing and adult brain. CELL PROLIFERATION CELL DIFFERENTIATION
  • 13. OTHER NEURAL STEM CELL MARKERS GFAP – marks astrocytes NeuN, βIII-tubulin – mark neurons GalC – marks oligodendrocytes DIFFERENTIATION MARKERS Musashi-1, Musashi-2, Pax3, Pax6, Hes1, Hes5, CD133, CD15, Vimentin
  • 14. CONTROVERSY Sorrells et al. found a sharp drop in neurogenesis as the human brain ages Boldrini et al. find persistent adult neurogenesis in humans into the eighth decade of life
  • 15. SORRELLS Maps of Ki-67+ (green) cells in the DG from samples of individuals that were between 22 gestational weeks and 35 years of age; GCL in blue. Ki-67+SOX1+ and Ki- 67+SOX2+ cells (arrows) are distributed across the hilus and GCL and the number of double-positive cells decreases between 22 gestational weeks and 1 year of age.
  • 16. DCX+PSA-NCAM+ cells in the DG from birth to the age of 77 showing that the number of young neurons declines in the human DG
  • 17. BOLDRINI (A and B) Co-expression of Sox2 and nestin in QNPs. (E) GFAP+ cells with apical process (white arrow) nestin+ INP (yellow arrow). (F) Nestin/Ki-67+ INP.
  • 18. (M) Sox2+ cell decline in anterior-mid DG with aging. (N and O) Nestin+ and Ki-67+ cells do not decline with older age in anterior, mid, or posterior DG.
  • 19. (A) PSA-NCAM and DCX expression in an immature neuron between subgranular zone (SGZ) and granule cell layer (GCL), two PSA-NCAM+/DCX cells, and 4’,6- diamidino-2-phenylindole (DAPI)+ nuclei. (G–H) Stable DCX+ immature neurons, NeuN+ mature granule neurons
  • 20. ISSUES RAISED Post Mortem Delay - PMD. Boldrini’s study sample size age group DCX as a marker? Sorrells used patients who had epilepsy Use of 10% formalin Gerd Kempermann
  • 21. There have been studies conducted after this controversy as well (in 2019) that lean towards Boldrini’s conclusion that neurogenesis does persist through an older age in healthy individuals as well as in patients suffering from mild cognitive impairments (MCI) and Alzheimer’s Disease. Tobin et al. observe persistent hippocampal neurogenesis in aging brains with no cognitive impairments, mild cognitive impairments, and Alzheimer’s disease. Elena P. Moreno-Jiménez et al. observe persistence of adult hippocampal neurons during both physiological and pathological aging in humans
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