Transcription factors expressed in embryonic and adult olfactory bulb neural stem cells reveal distinct proliferation, differentiation and epigenetic control

AbstractFatty acids are well known as important constituents for the synthesis of membrane lipids and as sources of cellular energy in the CNS. However, fatty acids can also act as vital second messenger molecules in the nervous system and regulate the activity of many proteins affecting cell growth and survival. Here, we show that an essential dietary fatty acid, Decosahexaenoic acid, (DHA), can enhance stem cell function in vitro and in vivo. We found that this effect is not due to an increase in the overall proliferation rate of all neural progenitors, but is due to an increase in the number of multipotent stem cells that leads to greater levels of subventricular zone (SVZ) neurogenesis with restoration of olfactory function in aged mice. These effects were likely mediated through increased EGF-receptor sensitivity, a conversion of EGRFR+ progenitors back into an EGRFR+/GFAP+ stem cell state, and the activation of the PI3K/AKT signaling pathway, which is a critical pathway in many NSC cell functions including cell growth and survival. Together these data demonstrate that neural stem cells in the aged and quiescent neurogenic niche of the mouse SVZ retain their ability to self-renew and contribute to neurogenesis when apparently rejuvenated by DHA and PI3K/AKT pathway activation. DHA stimulation of this signaling enhances the number of multipotent stem cells and neurogenesis in young and aged rodent and human stem cells and hence may have implications for the manipulation of neural stem cells for brain repair.Significance StatementWe have identified potentially important effects of DHA on the stem cell population which may be unique to the SVZ stem cell niche. Our studies demonstrate that DHA can promote the production of neural stem cells, possibly via a non-proliferative mechanism stimulated by EGF receptor activation, and prolongs their viability. Aging animals undergo an apparent loss in SVZ stem cells and an associated decline in olfactory bulb function. We find that dietary DHA supplementation at least partially restores stem cell numbers, olfactory bulb neurogenesis and olfactory discrimination and memory in aged mice, demonstrating a capacity for rejuvenation is retained despite age-related changes to the niche, which has significant implications for ameliorating cognitive decline in aging and for endogenous brain repair.

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Spatio-Temporal Recruitment Of Adult Neural Stem Cells For Transient Neurogenesis During Pregnancy

10.1101/2021.07.11.451957 ◽

2021 ◽

Author(s):

Zayna Chaker ◽

Corina Segalada ◽

Fiona Doetsch

Keyword(s):

Stem Cells ◽

Olfactory Bulb ◽

Neural Stem Cells ◽

Adult Mouse ◽

Life Experiences ◽

Brain Plasticity ◽

Perinatal Care ◽

Adult Mouse Brain ◽

Spatio Temporal ◽

Care Period

Neural stem cells (NSCs) in the adult mouse brain contribute to lifelong brain plasticity. NSCs in the adult ventricular-subventricular zone (V-SVZ) are heterogeneous and, depending on their location in the niche, give rise to different subtypes of olfactory bulb interneurons. Here, we show that during pregnancy multiple regionally-distinct NSCs are dynamically recruited at different times. Coordinated temporal activation of these NSC pools generates sequential waves of short-lived olfactory bulb interneuron subtypes that mature in the mother around birth and in the perinatal care period. Concomitant with neuronal addition, oligodendrocyte progenitors also transiently increase in the olfactory bulb. Thus, life experiences, such as pregnancy, can trigger transient neurogenesis and gliogenesis under tight spatial and temporal control, and may provide a novel substrate for brain plasticity in anticipation of temporary physiological demand.

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Therapeutic potential of human olfactory bulb neural stem cells for spinal cord injury in rats

Spinal Cord ◽

10.1038/sc.2016.14 ◽

2016 ◽

Vol 54 (10) ◽

pp. 785-797 ◽

Cited By ~ 6

Author(s):

H E Marei ◽

A Althani ◽

S Rezk ◽

A Farag ◽

S Lashen ◽

...

Keyword(s):

Spinal Cord ◽

Stem Cells ◽

Spinal Cord Injury ◽

Olfactory Bulb ◽

Neural Stem Cells ◽

Therapeutic Potential ◽

Cord Injury

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Direct Reprogramming of Mouse Fibroblasts to Neural Stem Cells by Small Molecules

Stem Cells International ◽

10.1155/2016/4304916 ◽

2016 ◽

Vol 2016 ◽

pp. 1-11 ◽

Cited By ~ 23

Author(s):

Yan-Chuang Han ◽

Yoon Lim ◽

Michael D. Duffieldl ◽

Hua Li ◽

Jia Liu ◽

...

Keyword(s):

Stem Cells ◽

Transcription Factors ◽

Neural Stem Cells ◽

Small Molecules ◽

Clinical Medicine ◽

Viral Vector ◽

Expression Patterns ◽

Tumor Formation ◽

Patient Specific ◽

Mouse Fibroblasts

Although it is possible to generate neural stem cells (NSC) from somatic cells by reprogramming technologies with transcription factors, clinical utilization of patient-specific NSC for the treatment of human diseases remains elusive. The risk hurdles are associated with viral transduction vectors induced mutagenesis, tumor formation from undifferentiated stem cells, and transcription factors-induced genomic instability. Here we describe a viral vector-free and more efficient method to induce mouse fibroblasts into NSC using small molecules. The small molecule-induced neural stem (SMINS) cells closely resemble NSC in morphology, gene expression patterns, self-renewal, excitability, and multipotency. Furthermore, the SMINS cells are able to differentiate into astrocytes, functional neurons, and oligodendrocytesin vitroandin vivo. Thus, we have established a novel way to efficiently induce neural stem cells (iNSC) from fibroblasts using only small molecules without altering the genome. Such chemical induction removes the risks associated with current techniques such as the use of viral vectors or the induction of oncogenic factors. This technique may, therefore, enable NSC to be utilized in various applications within clinical medicine.

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PPARs Expression in Adult Mouse Neural Stem Cells: Modulation of PPARs during Astroglial Differentiaton of NSC

PPAR Research ◽

10.1155/2007/48242 ◽

2007 ◽

Vol 2007 ◽

pp. 1-10 ◽

Cited By ~ 22

Author(s):

A. Cimini ◽

L. Cristiano ◽

E. Benedetti ◽

B. D'Angelo ◽

M. P. Cerù

Keyword(s):

Cell Cycle ◽

Stem Cells ◽

Cell Proliferation ◽

Transcription Factors ◽

Neural Stem Cells ◽

Osteoblast Differentiation ◽

Adult Mouse ◽

Cell Type ◽

Cell Proliferation And Differentiation ◽

Proliferation And Differentiation

PPAR isotypes are involved in the regulation of cell proliferation, death, and differentiation, with different roles and mechanisms depending on the specific isotype and ligand and on the differentiated, undifferentiated, or transformed status of the cell. Differentiation stimuli are integrated by key transcription factors which regulate specific sets of specialized genes to allow proliferative cells to exit the cell cycle and acquire specialized functions. The main differentiation programs known to be controlled by PPARs both during development and in the adult are placental differentiation, adipogenesis, osteoblast differentiation, skin differentiation, and gut differentiation. PPARs may also be involved in the differentiation of macrophages, brain, and breast. However, their functions in this cell type and organs still awaits further elucidation. PPARs may be involved in cell proliferation and differentiation processes of neural stem cells (NSC). To this aim, in this work the expression of the three PPAR isotypes and RXRs in NSC has been investigated.

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