Regulatory Roles of Bone in Neurodegenerative Diseases

Osteoporosis and neurodegenerative diseases are two kinds of common disorders of the elderly, which often co-occur. Previous studies have shown the skeletal and central nervous systems are closely related to pathophysiology. As the main structural scaffold of the body, the bone is also a reservoir for stem cells, a primary lymphoid organ, and an important endocrine organ. It can interact with the brain through various bone-derived cells, mostly the mesenchymal and hematopoietic stem cells (HSCs). The bone marrow is also a place for generating immune cells, which could greatly influence brain functions. Finally, the proteins secreted by bones (osteokines) also play important roles in the growth and function of the brain. This article reviews the latest research studying the impact of bone-derived cells, bone-controlled immune system, and bone-secreted proteins on the brain, and evaluates how these factors are implicated in the progress of neurodegenerative diseases and their potential use in the diagnosis and treatment of these diseases.

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The Role of Dietary Antioxidants in the Pathogenesis of Neurodegenerative Diseases and Their Impact on Cerebral Oxidoreductive Balance

Nutrients ◽

10.3390/nu12020435 ◽

2020 ◽

Vol 12 (2) ◽

pp. 435 ◽

Cited By ~ 4

Author(s):

Anna Winiarska-Mieczan ◽

Ewa Baranowska-Wójcik ◽

Małgorzata Kwiecień ◽

Eugeniusz R. Grela ◽

Dominik Szwajgier ◽

...

Keyword(s):

Neurodegenerative Diseases ◽

Negative Impact ◽

Functional Disorders ◽

Brain Functions ◽

Diet Supplements ◽

The Impact ◽

The Brain ◽

All Diseases

Neurodegenerative diseases are progressive diseases of the nervous system that lead to neuron loss or functional disorders. Neurodegenerative diseases require long-term, sometimes life-long pharmacological treatment, which increases the risk of adverse effects and a negative impact of pharmaceuticals on the patients’ general condition. One of the main problems related to the treatment of this type of condition is the limited ability to deliver drugs to the brain due to their poor solubility, low bioavailability, and the effects of the blood-brain barrier. Given the above, one of the main objectives of contemporary scientific research focuses on the prevention of neurodegenerative diseases. As disorders related to the competence of the antioxidative system are a marker in all diseases of this type, the primary prophylactics should entail the use of exogenous antioxidants, particularly ones that can be used over extended periods, regardless of the patient’s age, and that are easily available, e.g., as part of a diet or as diet supplements. The paper analyzes the significance of the oxidoreductive balance in the pathogenesis of neurodegenerative diseases. Based on information published globally in the last 10 years, an analysis is also provided with regard to the impact of exogenous antioxidants on brain functions with respect to the prevention of this type of diseases.

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Characterization of Hematopoietic Stem Cell Frequency and Function In Unexplained Anemia of the Elderly

Blood ◽

10.1182/blood.v116.21.2047.2047 ◽

2010 ◽

Vol 116 (21) ◽

pp. 2047-2047

Author(s):

Wendy Pang ◽

Elizabeth Price ◽

Irving L. Weissman ◽

Stanley L. Schrier

Keyword(s):

Stem Cells ◽

Bone Marrow ◽

In Vitro Culture ◽

Progenitor Cells ◽

The Elderly ◽

Elderly Subjects ◽

Hematopoietic Stem ◽

Stem And Progenitor Cells ◽

And Function

Abstract Abstract 2047 Anemia is both a highly prevalent and clinically important condition that causes significant morbidity and mortality in the elderly population. While anemia in the elderly can be attributed to a number of causes, approximately 30% of elderly subjects with anemia have no overt etiology and fall under the category of unexplained anemia of the elderly (UA). There is increasing evidence to suggest that changes in the frequency and/or function of hematopoietic stem and progenitor cells may contribute to the onset and pathophysiology of age-associated hematological conditions, such as UA. Hematopoietic stem cells (HSC) reside at the top of the hematopoietic hierarchy and can differentiate, via increasingly committed downstream progenitors, into all the mature cells of the hematopoietic system. Human myelo-erythroid development proceeds through a set of oligopotent progenitors: HSC give rise to multipotent progenitors (MPP), which give rise to common myeloid progenitors (CMP), which in turn give rise to granulocyte-macrophage progenitors (GMP) and megakaryocyte-erythrocyte progenitors (MEP). We use flow cytometry and in vitro culture of sorted human HSC (Lin-CD34+CD38-CD90+CD45RA-), MPP (Lin-CD34+CD38-CD90-CD45RA-), CMP (Lin-CD34+CD38+CD123+CD45RA-), GMP (Lin-CD34+CD38+CD123+CD45RA+), and MEP (Lin-CD34+CD38+CD123-CD45RA-) from hematologically normal young (23 samples; age 20–35) and elderly (11 samples; age 65+) and UA (5 samples; age 65+) bone marrow samples in order to characterize the changes in the distribution and function of hematopoietic stem and progenitor populations during the aging process and, in particular, in the development of UA. We found that UA patients contain higher frequencies of HSC compared to both elderly normal (1.5-fold; p<0.03) and young normal samples (2.8-fold; p<10-5). We also found increased frequencies of MPP from UA patients compared to MPP from elderly normal (2.6-fold; p<0.002) and young normal samples (5.8-fold; p<0.04). While we observed similar frequencies of CMP among the three groups, we found a notable trend suggesting decreased frequencies of GMP and corresponding increased frequencies of MEP in UA patients. Functionally, HSC from the three groups exhibit statistically insignificant differences in the efficiency of colony formation under the myeloid differentiation-promoting methylcellulose-based in vitro culture conditions; however, on average, HSC from elderly bone marrow samples, regardless of the presence or absence of anemia, tend to form fewer colonies in methylcellulose. Interestingly, HSC from UA patients produce more granulocyte-monocyte (CFU-GM) colonies and fewer erythroid (CFU-E and BFU-E) colonies, compared to HSC from normal samples (p<0.001). Similarly, CMP from UA patients, compared to normal CMP, yield skewed distributions of myeloid-erythroid colonies when plated in methylcellulose, significantly favoring production of CFU-GM colonies over CFU-E and BFU-E colonies (p<0.003). Additionally, MEP from UA patients form both CFU-E and BFU-E colonies in methylcellulose albeit at a significantly lower efficiency than MEP from normal bone marrow samples (p<0.01). This is the first study to examine the changes in hematopoietic stem and progenitor populations in UA patients. The changes in the distribution of hematopoietic stem and progenitor cells in UA patients indicate that the HSC and MPP populations, and possibly also the MEP population, expand in the context of anemia, potentially in response to homeostatic feedback mechanisms. Nevertheless, these expanded populations are functionally impaired in their ability to differentiate towards the erythroid lineage. Our data suggest that there are intrinsic defects in the HSC population of UA patients that lead to poor erythroid differentiation, which can be readily observed even in the earliest committed myelo-erythroid progenitors. We have generated gene expression profiling data from these purified hematopoietic stem and progenitor populations from UA patients to try to identify biological pathways and markers relevant to disease pathogenesis and potential therapeutic targets. Disclosures: Weissman: Amgen, Systemix, Stem cells Inc, Cellerant: Consultancy, Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Schrier:Celgene: Research Funding.

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Stem Cell Therapy for Neurodegenerative Diseases: How Do Stem Cells Bypass the Blood-Brain Barrier and Home to the Brain?

Stem Cells International ◽

10.1155/2020/8889061 ◽

2020 ◽

Vol 2020 ◽

pp. 1-8

Author(s):

Yvonne Cashinn Chia ◽

Clarice Evey Anjum ◽

Hui Rong Yee ◽

Yenny Kenisi ◽

Mike K. S. Chan ◽

...

Keyword(s):

Stem Cells ◽

Neurodegenerative Diseases ◽

Blood Brain Barrier ◽

Cellular Therapy ◽

Immune Cell ◽

Brain Barrier ◽

Normal Brain ◽

Brain Functions ◽

Blood Brain ◽

The Brain

Blood-brain barrier (BBB) is a term describing the highly selective barrier formed by the endothelial cells (ECs) of the central nervous system (CNS) homeostasis by restricting movement across the BBB. An intact BBB is critical for normal brain functions as it maintains brain homeostasis, modulates immune cell transport, and provides protection against pathogens and other foreign substances. However, it also prevents drugs from entering the CNS to treat neurodegenerative diseases. Stem cells, on the other hand, have been reported to bypass the BBB and successfully home to their target in the brain and initiate repair, making them a promising approach in cellular therapy, especially those related to neurodegenerative disease. This review article discusses the mechanism behind the successful homing of stem cells to the brain, their potential role as a drug delivery vehicle, and their applications in neurodegenerative diseases.

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Neural Stem Cells Therapy to Treat Neurodegenerative Diseases

E3S Web of Conferences ◽

10.1051/e3sconf/202127103076 ◽

2021 ◽

Vol 271 ◽

pp. 03076

Author(s):

Weibai Chen

Keyword(s):

Stem Cells ◽

Stem Cell ◽

Stem Cell Transplantation ◽

Neural Stem Cells ◽

Neurodegenerative Diseases ◽

Cell Transplantation ◽

Neural Stem Cell ◽

The Body ◽

Brain Diseases ◽

The Brain

Neural stem cells have the ability to proliferation, differentiate and renew, which plays an important role in the growth, maturation and senescence of the human brain. But according to researches, neural stem cells in the brain do not remain active throughout an organism's lifetime. Many neural stem cells become dormant when the brain matures, and may be activated when the body is sick to selectively heal the disease. In recent years, there are many studies on neural stem cells. Joshua[1] and Ting Zhang[2] show that neurodegenerative diseases such as ischemic stroke, Alzheimer's disease and Parkinson's disease can be improved by the transplantation of neural stem cells, however the specific mechanism is not clear. This paper investigates three main questions: Why neural stem cell transplantation is chosen as a treatment? Where does NSCs derive from in clinical transplantation? How does neural stem cell transplantation treat brain diseases? And we also figure out the answers to these three questions. Firstly, transplantation of hypothalamic NSCs can delay the process of aging in the host, and Chemokines and EVs which secreted by neural stem cells can delay aging and defend neurodegenerative diseases. Secondly, the sources of NSCs can be divided into three types. The first is to isolate NSCs from primary tissue and cultivate them in vitro. The second is to produce the required cells by inducing pluripotent stem cells and embryonic stem cells. The third way to get NCS is through transdifferentiation of somatic cells. Thirdly, in brain diseases, transplanted NSCs can migrate from the aggregation site to the site of the disease, reducing damage to the blood-brain barrier, repairing learning and memory abilities that depend on the hippocampus and secreting neurotrophic factors.

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The Impact of Neural Stem Cell Biology on CNS Carcinogenesis and Tumor Types

Pathology Research International ◽

10.4061/2011/685271 ◽

2011 ◽

Vol 2011 ◽

pp. 1-4 ◽

Cited By ~ 1

Author(s):

K. M. Kurian

Keyword(s):

Stem Cells ◽

Stem Cell ◽

Neural Stem Cell ◽

Cell Biology ◽

The Body ◽

Proliferative Potential ◽

Stem Cell Biology ◽

Tumor Types ◽

The Impact ◽

The Brain

The incidence of gliomas is on the increase, according to epidemiological data. This increase is a conundrum because the brain is in a privileged protected site behind the blood-brain barrier, and therefore partially buffered from environmental factors. In addition the brain also has a very low proliferative potential compared with other parts of the body. Recent advances in neural stem cell biology have impacted on our understanding of CNS carcinogenesis and tumor types. This article considers the cancer stem cell theory with regard to CNS cancers, whether CNS tumors arise from human neural stem cells and whether glioma stem cells can be reprogrammed.

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Bone-Derived Modulators That Regulate Brain Function: Emerging Therapeutic Targets for Neurological Disorders

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.683457 ◽

2021 ◽

Vol 9 ◽

Author(s):

Hongzhen Chen ◽

Dewei Shang ◽

Yuguan Wen ◽

Chao Liang

Keyword(s):

Stem Cells ◽

Neurological Disorders ◽

Brain Function ◽

The Body ◽

Whole Body ◽

Lipocalin 2 ◽

Hematopoietic Stem ◽

Bone Marrow Derived Cells ◽

Whole Body Metabolism ◽

And Function

Bone has traditionally been regarded as a structural organ that supports and protects the various organs of the body. Recent studies suggest that bone also acts as an endocrine organ to regulate whole-body metabolism. Particularly, homeostasis of the bone is shown to be necessary for brain development and function. Abnormal bone metabolism is associated with the onset and progression of neurological disorders. Recently, multiple bone-derived modulators have been shown to participate in brain function and neurological disorders, including osteocalcin, lipocalin 2, and osteopontin, as have bone marrow-derived cells such as mesenchymal stem cells, hematopoietic stem cells, and microglia-like cells. This review summarizes current findings regarding the roles of these bone-derived modulators in the brain, and also follows their involvement in the pathogenesis of neurological disorders. The content of this review may aide in the development of promising therapeutic strategies for neurological disorders via targeting bone.

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The Brain-Bone-Blood Triad: Traffic Lights for Stem-Cell Homing and Mobilization

Hematology ◽

10.1182/asheducation-2010.1.1 ◽

2010 ◽

Vol 2010 (1) ◽

pp. 1-6 ◽

Cited By ~ 59

Author(s):

Tsvee Lapidot ◽

Orit Kollet

Keyword(s):

Stem Cells ◽

Bone Marrow ◽

Immune Cell ◽

Severe Combined Immunodeficiency ◽

The Body ◽

Hematopoietic Stem ◽

Traffic Lights ◽

Stromal Cell Derived Factor ◽

Stress Signals ◽

The Brain

Abstract Navigation of transplanted stem cells to their target organs is essential for clinical bone marrow reconstitution. Recent studies have established that hematopoietic stem cells (HSCs) dynamically change their features and location, shifting from quiescent and stationary cells anchored in the bone marrow to cycling and motile cells entering the circulation. These changes are driven by stress signals. Bidirectional migrations to and from the bone marrow are active processes that form the basis for HSC transplantation protocols. However, how and why HSCs enter and exit the bone marrow as part of host defense and repair is not fully understood. The development of functional, preclinical, immune-deficient NOD/SCID (non-obese diabetic-severe combined immunodeficiency) mice transplantation models has enabled the characterization of normal and leukemic human HSCs and investigation of their biology. Intensive research has revealed multiple tasks for the chemokine SDF-1 (stromal cell-derived factor-1, also known as CXCL12) in HSC interactions with the microenvironment, as well as the existence of overlapping mechanisms controlling stress-induced mobilization and enhanced HSC homing, sequential events of major physiological relevance. These processes entail dynamically interacting, multi-system aspects that link the bone marrow vasculature and stromal cells with the nervous and immune systems. Neural cues act as an external pacemaker to synchronize HSC migration and development to balance bone remodeling via circadian rhythms in order to address blood and immune cell production for the physiological needs of the body. Stress situations and clinical HSC mobilization accelerate leukocyte proliferation and bone turnover. This review presents the concept that HSC regulation by the brain-bone-blood triad via stress signals controls the bone marrow reservoir of immature and maturing leukocytes.

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Prolonged self-renewal activity unmasks telomerase control of telomere homeostasis and function of mouse hematopoietic stem cells

Blood ◽

10.1182/blood-2010-11-319632 ◽

2011 ◽

Vol 118 (7) ◽

pp. 1766-1773 ◽

Cited By ~ 11

Author(s):

Sanja Sekulovic ◽

Vala Gylfadottir ◽

Irma Vulto ◽

Maura Gasparetto ◽

Yasmine Even ◽

...

Keyword(s):

Stem Cells ◽

Hematopoietic Stem Cells ◽

Self Renewal ◽

Telomere Shortening ◽

Hematopoietic Stem ◽

Telomere Homeostasis ◽

And Function ◽

The Impact

Abstract Strategies for expanding hematopoietic stem cells (HSCs) could have significant utility for transplantation-based therapies. However, deleterious consequences of such manipulations remain unknown. Here we examined the impact of HSC self-renewal divisions in vitro and in vivo on their subsequent regenerative and continuing ability to sustain blood cell production in the absence of telomerase. HSC expansion in vitro was obtained using a NUP98-HOXA10hd transduction strategy and, in vivo, using a serial transplant protocol. We observed ∼ 10kb telomere loss in leukocytes produced in secondary mice transplanted with HSCs regenerated in primary recipients of NUP98-HOXA10hd-transduced and in vitro-expanded Tert−/− HSCs 6 months before. The second generation leukocytes also showed elevated expression of γH2AX (relative to control) indicative of greater accumulating DNA damage. In contrast, significant telomere shortening was not detected in leukocytes produced from freshly isolated, serially transplanted wild-type (WT) or Tert−/− HSCs, suggesting that HSC replication posttransplant is not limited by telomere shortening in the mouse. These findings document a role of telomerase in telomere homeostasis, and in preserving HSC functional integrity on prolonged self-renewal stimulation.

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