Novel Balance Mechanism Participates in Stem Cell Therapy to Alleviate Neuropathology and Cognitive Impairment in Animal Models with Alzheimer’s Disease
Abstract
:1. Alzheimer’s Disease and Stem Cell Therapy
2. Participant Cell Types of New Balance Mechanism
- (1).
- Physical pressure. The local pressure of cerebral tissue can be increased after the stem cells are delivered through the intrahippocampal injection, but the same phenomenon is not found via the peripheral delivery. Nonetheless, the local physical pressure caused by mechanical force is almost negligible, since a similar therapeutic effects can be obtained through tail vein delivery as well [9,30,31].
- (2).
- Signaling molecules. The transportation of stem cells alters the microenvironment of cerebral tissue and stimulates the secretion of autocrine and paracrine cytokines, such as chemokines, leucocyte chemoattractant factors, transcription factors, inflammatory cytokines, fibrogenic cytokines, and growth factors (Table 1). Some factors are general products that can be secreted by all types of stem cells, whereas other cytokines are only produced by specific stem cells [32]. Those pragmatic cytokines participate in the establishment of new balance mechanisms. The secretion of autocrine and paracrine cytokines plays important roles in neurogenesis and synaptogenesis.
- (3).
- (a)
- Functional neurons play a central role in the brain. There are roughly 20 billion neurons in the human cortex. Each neuron has an average 7000 synaptic connections [33]. The number of synapses is relatively stabilized in adulthood. Neuronal synapses may decrease with aging, but they can also increase due to brain plasticity. The transplanted stem cells can stimulate neurogenesis and synapse formation. Newborn neurons may be from (i) the transdifferentiation of stem cells; and (ii) the activation of specialized multipotent stem cells in the brain. At present, stem cell therapy has overcome the concerns of uncertainty and safety, and its effectiveness has been validated as well.
- (b)
- Oligodendrocyte is a specific subtype of neuroglia. In the central nervous system, their branch structures wrap around the neuronal axons to form an insulating myelin sheath. The physiological function of oligodendrocytes is to maintain neuronal insulation during the excitement of nerve signals. The complete structure of the myelin sheath provides a safety measure for signal transmission among neuronal synapses. Stem cell therapy restores neuronal networks by way of synaptogenesis that is protected by the myelin sheaths from oligodendrocytes [34,35].
- (c)
- Astrocytes, also called astroglia, have projections covering local neurons. Astrocytes are the support system in the cerebral tissue to hold neurons in the position. Additionally, they can produce cytokines and interact with other cell types. For example, astrocytes participate in microglia-mediated inflammatory and immune processes [36]. Astrocytes are responsible for substance exchange. In the CNS, astrocytes contact both capillaries and neurons to transport nutrients. Moreover, the phagocytosis of astrocytes is implicated in the amyloid load of Alzheimer disease [37]. In the process of stem cell therapy, the precise roles of astrocytes are still unclear. After exposure to MSC-conditioned medium, the expression of pro-inflammatory factors such as IL-1β, TNF-α and IL-6 was attenuated in cultured astrocytes [38]. The transplanted stem cells acted on astrocytes to modify neuroimmune and relieve neuroinflammation in vivo [39].
- (d)
- Microglia are resident immune cells in the brain, equivalent to macrophages. Functional microglia take part in the neuroinflammation, immunomodulation, the elimination of Aβ proteins, and tau pathology. As the first line of the neuroimmune system, microglia remove cerebral debris and protect neurons from harmful invasion. In contrast, the inflammatory factors released by microglia can cause receptor-induced neuronal apoptosis [40]. Fortunately, microglial activity can be modulated by the transplanted stem cells. So, stem cell therapy suppresses neuroinflammation and controls neuroimmune overreaction. Furthermore, microglia can detect neuronal injury and play a critical role in the maintenance of neuronal health. As immune cells, microglia have duality in the pathogenesis of AD. They can not only protect neurons by engulfing detrimental Aβ proteins, but also damage neurons by secreting inflammatory cytokines [41,42,43]. The consequence may be beneficial or pernicious, which is determined by the comprehensive effect of multi-level signaling crosstalk.
3. Representative Signaling Pathways of New Balance Mechanism
3.1. The Transplantation of Stem Cells Mediates Cell Growth and Death
3.2. The Transplanted Stem Cells Regulate the Production and Removal of Aberrant Proteins
3.3. The Transplanted Stem Cells Can Produce Pro- and Anti-Inflammatory Cytokines
3.4. Immunoregulation Is Modulated by the Transplanted Stem Cells
3.5. The Transplanted Stem Cells Participate in Synaptic Plasticity
4. Perspective
4.1. Therapeutic Efficiency and Synergistic Effect
4.2. Stem Cell Viability
4.3. The Improvement of Delivery Methods
4.4. Exosomes
5. Challenges
- (1).
- The selection of surveillance biomarkers. Currently, monitoring markers (i.e., Aβ42, T-tau and P-tau, or exosomes in cerebrospinal fluid and/or peripheral bloodstream) need to be optimized for the evaluation of therapeutic effects.
- (2).
- The timeline of the new balance mechanism. Following the transplantation of stem cells, the pathological state is altered and then a new balance is developed. However, it is unsure how long the dynamic reconstruction can be maintained. Perhaps, it is necessary to repeatedly transplant stem cells to obtain reliable therapeutic effects. At this time, it is important to optimize the relevant parameters of stem cell transplantation, including cell concentration, time interval, inoculation position, and delivery method.
- (3).
- Uncertainty and perplexity. The therapeutic effect of transplanted stem cells involves multiple mechanisms, such as immunomodulation, inflammation, apoptosis, neurogenesis, autophagy, and angiogenesis. The integration of various mechanisms establishes a new balance and brings about beneficial improvements. Nowadays, most of the above-mentioned mechanisms have been investigated and their roles have been elucidated. Nevertheless, the details of relevant mechanisms still need to be explored, such as autophagy and immunomodulation, the interaction between astrocytes and microglia, microglial activation and synaptic remodeling, etc.
Author Contributions
Funding
Conflicts of Interest
Abbreviations
References
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Fibrogenic cytokines | FGF, TIMP-1 | Proliferation of fibroblasts, collagen synthesis and extracellular fibrosis, immune mediators. | PLoS ONE. 2019 Apr 22;14(4):e0215678; Brain Res. 2004 Apr 16;1005(1–2):21–8. |
Chemokines | CCL5, CXCL-10, CXCL-12, | Chemo-attractants, to guide the migration of cells, to regulate immunity, inflammation, angiogenesis, etc. | Stem Cells. 2012 Jul;30(7):1544–55; Cancer Res. 2011 Jun 1;71(11):3831–40; J. Cell Physiol. 2019 Aug;234(10):18707–18719 |
Leucocyte chemoattractant factors | CINC-1, G-CSF, SCF, GM-CSF | To participate in immune/inflammatory cascade. | PLoS ONE. 2019 Apr 22;14(4):e0215678; Blood. 2000 Nov 15;96(10):3422–30. |
Transcription factors | GATA-4, Nkx2.5, MEF2C | Response to intercellular and extracellular signals, transcriptional regulation in development, cell cycle, and pathogenesis. | Mol. Med. Rep. 2015 Aug;12(2):2607–21; Tissue Eng. Part A. 2011 Jan;17(1–2):45–58. |
Growth factors | HGF, IGF-1 | Signaling molecules promote cell differentiation and maturation. | Stem Cells Dev. 2010 Jul;19(7):1035–42; Int. J. Stem Cells. 2009 May;2(1):59–68. |
Vascular endothelial growth factor | VEGF | To stimulate the formation of blood vessels. | Int. J. Stem Cells. 2009 May;2(1):59–68; Brain Res. 2004 Apr 16;1005(1–2):21–8. |
Other | MCP-1, OPG | Selectively recruiting monocytes, to regulate bone metabolism. | Int. J. Stem Cells. 2009 May;2(1):59–68; J. Interferon Cytokine Res. 2009 Jun;29(6):313–26; Cell. 1997 Apr 18;89(2):309–19. |
Mechanisms | Cell Types | Signaling Pathways | References |
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Immunoregulation | Neurons, Microglia, Astrocytes, Oligodendrocytes | To facilitate microglial M1/M2 polarization; to regulate the crosstalk between T cells and microglia; to mediate synaptic plasticity. | Neuroscience. 2019 Dec 1;422:99–118; Proc. Natl. Acad. Sci. USA. 2006 Mar 28;103(13): 5048–5053; Front. Synaptic Neurosci. 2018 Jun 13;10:14. |
Inflammation | Neurons, Microglia, Astrocytes, Oligodendrocytes | To decrease the level of NF-κB in astrocytes; to reduce the levels of TNF-α, IL-6, and MCP-1; to regulate cell growth and apoptosis. | Neuropathol. Appl. Neurobiol. 2017 Jun;43(4):299–314; Sci. Rep. 2020 Jul 1;10(1):10772; DOI:10.1186/s13024-015-0035-6. |
Neurogenesis | Neurons, Microglia, Astrocytes, Oligodendrocytes | To increase IGF-1 expression in the hippocampus; to increase N-acetylaspartate and Glutamate; to induce the expression of synaptophysin. | Exp. Ther. Med. 2017 Nov; 14(5): 4312–4320; Transl. Neurodegener. 2020 May 27;9(1):20; Hippocampus. 2017 Dec;27(12):1250–1263 |
Autophagy | Neurons, Microglia, Astrocytes, Oligodendrocytes | To increase cellular viability and LC3-II expression; to upregulate BECN1/Beclin 1 expression; to enhance mitophagy. | Autophagy. 2014 Jan;10(1):32–44; Mol. Neurobiol. 2019 Dec;56(12):8220–8236; Autophagy. 2021 Jan 19;1–20. |
Apoptosis | Neurons, Microglia, Astrocytes, Oligodendrocytes | To regulate expression of hippocampal SIRT1, PCNA, p53, ac-p53, p21, and p16; to target caspase pathway; Ca2+ signaling. | Behav. Brain Res. 2018 Feb 26;339:297–304; Front. Neurosci. 2018 May 22;12:333; Curr. Alzheimer Res. 2010 Sep;7(6):540–8; Sci. Rep. 2016 Aug 12;6:31450. |
Angiogenesis | Neurons, Microglia, Astrocytes, Oligodendrocytes | BMSCs secrete VEGF, BDNF, NT-3, IGF-1, bFGF, GDNF and TGF. VEGF is the most important mitogen in the process of angiogenesis. | Brain Res. 2011 Jan 7; 1367:103–113; Int. J. Mol. Med. 2013 May;31(5):1087–96; Neuroreport. 2015 May 6;26(7):399–404. |
Synaptogenesis | Neurons, Microglia, Astrocytes, Oligodendrocytes | To stimulate the production of BDNF and NGF for remyelination; peptide FG loop (FGL) amplifies remyelination and modulates neuroinflammation. | Cell Biol. Int. 2021 Feb;45(2):432–446; J. Neuroimmune. Pharmacol. 2016 Dec;11(4):708–720; Front. Cell Dev. Biol. 2021 Jul 2;9:680301. |
Names | Function | References |
---|---|---|
TREM2 | Transmembrane glycoprotein. To mediate immune and inflammatory responses as microglial receptor. | Neurobiol. Dis. 2020 Nov;145:105072; Neurobiol. Dis. 2019 Jul;127:432–448. |
CR1 | To regulate complement cascade and mediate immune adherence as well as phagocytosis. | Stem Cell Res. 2016 Nov;17(3):560–563. |
HLA-DRB5 | To encode major histocompatibility complex class II protein involved in immune responses. | Neurol. Genet. 2018 Jan 18;4(1):e211; JAMA Neurol. 2015 Jan;72(1):15–24. |
CD33 | Microglial receptor converged on immune-inflammatory pathways. | Neurobiol. Dis. 2019 Jul;127:432–448; Gerontology. 2019;65(4):323–331 |
MS4A | Belonging to a class of four-transmembrane spanning proteins. | Aging Cell. 2019 Aug;18(4):e12964. |
INPP5D | At the plasma membrane, the protein hydrolyzes the 5′ phosphate and regulates multiple signaling pathways. | EMBO Mol. Med. 2020 Mar 6;12(3):e10606. |
EPHA1 | To regulate the developmental of nervous system. | Int. J. Comput. Biol. Drug Des. 2020;13(1):58–70; J. Immunol. 2020 Sep 1;205(5):1318–1322. |
CLU | Diverse functions such as protein chaperoning, apoptosis, complement activation, etc. | Mol Neurodegener. 2015 Jul 16;10:30; Turk J Med Sci. 2015;45(5):1082–6. |
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Qin, C.; Li, Y.; Wang, K. Novel Balance Mechanism Participates in Stem Cell Therapy to Alleviate Neuropathology and Cognitive Impairment in Animal Models with Alzheimer’s Disease. Cells 2021, 10, 2757. https://doi.org/10.3390/cells10102757
Qin C, Li Y, Wang K. Novel Balance Mechanism Participates in Stem Cell Therapy to Alleviate Neuropathology and Cognitive Impairment in Animal Models with Alzheimer’s Disease. Cells. 2021; 10(10):2757. https://doi.org/10.3390/cells10102757
Chicago/Turabian StyleQin, Chuan, Yongning Li, and Kewei Wang. 2021. "Novel Balance Mechanism Participates in Stem Cell Therapy to Alleviate Neuropathology and Cognitive Impairment in Animal Models with Alzheimer’s Disease" Cells 10, no. 10: 2757. https://doi.org/10.3390/cells10102757