Neuroimmunology

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Neuroimmunology is a field combining neuroscience, the study of the nervous system, and immunology, the study of the immune system. Neuroimmunologists seek to better understand the interactions of these two complex systems during development, homeostasis, and response to injuries. A long-term goal of this rapidly developing research area is to further develop our understanding of the pathology of certain neurological diseases, some of which have no clear etiology. In doing so, neuroimmunology contributes to development of new pharmacological treatments for several neurological conditions. Many types of interactions involve both the nervous and immune systems including the physiological functioning of the two systems in health and disease, malfunction of either and or both systems that leads to disorders, and the physical, chemical, and environmental stressors that affect the two systems on a daily basis.

Contents

Background

Neural targets that control thermogenesis, behavior, sleep, and mood can be affected by pro-inflammatory cytokines which are released by activated macrophages and monocytes during infection. Within the central nervous system production of cytokines has been detected as a result of brain injury, during viral and bacterial infections, and in neurodegenerative processes.

From the US National Institute of Health: [1]

"Despite the brain's status as an immune privileged site, an extensive bi-directional communication takes place between the nervous and the immune system in both health and disease. Immune cells and neuroimmune molecules such as cytokines, chemokines, and growth factors modulate brain function through multiple signaling pathways throughout the lifespan. Immunological, physiological and psychological stressors engage cytokines and other immune molecules as mediators of interactions with neuroendocrine, neuropeptide, and neurotransmitter systems. For example, brain cytokine levels increase following stress exposure, while treatments designed to alleviate stress reverse this effect.

"Neuroinflammation and neuroimmune activation have been shown to play a role in the etiology of a variety of neurological disorders such as stroke, Parkinson's and Alzheimer's disease, multiple sclerosis, pain, and AIDS-associated dementia. However, cytokines and chemokines also modulate CNS function in the absence of overt immunological, physiological, or psychological challenges. For example, cytokines and cytokine receptor inhibitors affect cognitive and emotional processes. Recent evidence suggests that immune molecules modulate brain systems differently across the lifespan. Cytokines and chemokines regulate neurotrophins and other molecules critical to neurodevelopmental processes, and exposure to certain neuroimmune challenges early in life affects brain development. In adults, cytokines and chemokines affect synaptic plasticity and other ongoing neural processes, which may change in aging brains. Finally, interactions of immune molecules with the hypothalamic-pituitary-gonadal system indicate that sex differences are a significant factor determining the impact of neuroimmune influences on brain function and behavior."

Recent research demonstrates that reduction of lymphocyte populations can impair cognition in mice, and that restoration of lymphocytes restores cognitive abilities. [2]

Epigenetics

Overview

Epigenetic medicine encompasses a new branch of neuroimmunology that studies the brain and behavior, and has provided insights into the mechanisms underlying brain development, evolution, neuronal and network plasticity and homeostasis, senescence, the etiology of diverse neurological diseases and neural regenerative processes. It is leading to the discovery of environmental stressors that dictate initiation of specific neurological disorders and specific disease biomarkers. The goal is to "promote accelerated recovery of impaired and seemingly irrevocably lost cognitive, behavioral, sensorimotor functions through epigenetic reprogramming of endogenous regional neural stem cells". [3]

Neural stem cell fate

Several studies have shown that regulation of stem cell maintenance and the subsequent fate determinations are quite complex. The complexity of determining the fate of a stem cell can be best understood by knowing the "circuitry employed to orchestrate stem cell maintenance and progressive neural fate decisions". [4] Neural fate decisions include the utilization of multiple neurotransmitter signal pathways along with the use of epigenetic regulators. The advancement of neuronal stem cell differentiation and glial fate decisions must be orchestrated timely to determine subtype specification and subsequent maturation processes including myelination. [5]

Neurodevelopmental disorders

Neurodevelopmental disorders result from impairments of growth and development of the brain and nervous system and lead to many disorders. Examples of these disorders include Asperger syndrome, traumatic brain injury, communication, speech and language disorders, genetic disorders such as fragile-X syndrome, Down syndrome, ADHD, epilepsy, and fetal alcohol syndrome. Studies have shown that autism spectrum disorders (ASDs) may present due to basic disorders of epigenetic regulation. [6] Other neuroimmunological research has shown that deregulation of correlated epigenetic processes in ASDs can alter gene expression and brain function without causing classical genetic lesions which are more easily attributable to a cause and effect relationship. [7] These findings are some of the numerous recent discoveries in previously unknown areas of gene misexpression.

Neurodegenerative disorders

Increasing evidence suggests that neurodegenerative diseases are mediated by erroneous epigenetic mechanisms. Neurodegenerative diseases include Huntington's disease and Alzheimer's disease. Neuroimmunological research into these diseases has yielded evidence including the absence of simple Mendelian inheritance patterns, global transcriptional dysregulation, multiple types of pathogenic RNA alterations, and many more. [8] In one of the experiments, a treatment of Huntington’s disease with histone deacetylases (HDAC), an enzyme that removes acetyl groups from lysine, and DNA/RNA binding anthracylines that affect nucleosome positioning, showed positive effects on behavioral measures, neuroprotection, nucleosome remodeling, and associated chromatin dynamics. [9] Another new finding on neurodegenerative diseases involves the overexpression of HDAC6 suppresses the neurodegenerative phenotype associated with Alzheimer’s disease pathology in associated animal models. [10] Other findings show that additional mechanisms are responsible for the "underlying transcriptional and post-transcriptional dysregulation and complex chromatin abnormalities in Huntington's disease". [11]

Neuroimmunological disorders

The nervous and immune systems have many interactions that dictate overall body health. The nervous system is under constant monitoring from both the adaptive and innate immune system. Throughout development and adult life, the immune system detects and responds to changes in cell identity and neural connectivity. [12] Deregulation of both adaptive and acquired immune responses, impairment of crosstalk between these two systems, as well as alterations in the deployment of innate immune mechanisms can predispose the central nervous system (CNS) to autoimmunity and neurodegeneration. [13] Other evidence has shown that development and deployment of the innate and acquired immune systems in response to stressors on functional integrity of cellular and systemic level and the evolution of autoimmunity are mediated by epigenetic mechanisms. [14] Autoimmunity has been increasingly linked to targeted deregulation of epigenetic mechanisms, and therefore, use of epigenetic therapeutic agents may help reverse complex pathogenic processes. [15] Multiple sclerosis (MS) is one type of neuroimmunological disorder that affects many people. MS features CNS inflammation, immune-mediated demyelination and neurodegeneration.

Myalgic Encephalomyelitis (also known as Chronic fatigue syndrome), is a multi-system disease that causes dysfunction of neurological, immune, endocrine and energy-metabolism systems. Though many patients show neuroimmunological degeneration, the correct roots of ME/CFS are unknown. Symptoms of ME/CFS include significantly lowered ability to participate in regular activities, stand or sit straight, inability to talk, sleep problems, excessive sensitivity to light, sound or touch and/or thinking and memory problems (defective cognitive functioning). Other common symptoms are muscle or joint pain, sore throat or night sweats. There is no treatment but symptoms may be treated. Patients that are sensitive to mold may show improvement in symptoms having moved to drier areas. Some patients in general have less severe ME, whereas others may be bedridden for life. [16]

PTSD has been linked to neuroimmunity dysfunction with this being greater in individuals with worse anhedonia. [17]

Major themes of research

The interaction of the CNS and immune system are fairly well known. Burn-induced organ dysfunction using vagus nerve stimulation has been found to attenuate organ and serum cytokine levels. Burns generally induce abacterial cytokine generation and perhaps parasympathetic stimulation after burns would decrease cardiodepressive mediator generation. Multiple groups have produced experimental evidence that support proinflammatory cytokine production being the central element of the burn-induced stress response. [18] Still other groups have shown that vagus nerve signaling has a prominent impact on various inflammatory pathologies. These studies have laid the groundwork for inquiries that vagus nerve stimulation may influence postburn immunological responses and thus can ultimately be used to limit organ damage and failure from burn induced stress.

Basic understanding of neuroimmunological diseases has changed significantly during the last ten years. New data broadening the understanding of new treatment concepts has been obtained for a large number of neuroimmunological diseases, none more so than multiple sclerosis, since many efforts have been undertaken recently to clarify the complexity of pathomechanisms of this disease. Accumulating evidence from animal studies suggests that some aspects of depression and fatigue in MS may be linked to inflammatory markers. [19] Studies have demonstrated that Toll like-receptor (TLR4) is critically involved in neuroinflammation and T cell recruitment in the brain, contributing to exacerbation of brain injury. [20] Research into the link between smell, depressive behavior, and autoimmunity has turned up interesting findings including the facts that inflammation is common in all of the diseases analyzed, depressive symptoms appear early in the course of most diseases, smell impairment is also apparent early in the development of neurological conditions, and all of the diseases involved the amygdale and hippocampus. Better understanding of how the immune system functions and what factors contribute to responses are being heavily investigated along with the aforementioned coincidences.

Neuroimmunology is also an important topic to consider during the design of neural implants. Neural implants are being used to treat many diseases, and it is key that their design and surface chemistry do not elicit an immune response.

Future directions

The nervous system and immune system require the appropriate degrees of cellular differentiation, organizational integrity, and neural network connectivity. These operational features of the brain and nervous system may make signaling difficult to duplicate in severely diseased scenarios. There are currently three classes of therapies that have been utilized in both animal models of disease and in human clinical trials. These three classes include DNA methylation inhibitors, HDAC inhibitors, and RNA-based approaches. DNA methylation inhibitors are used to activate previously silenced genes. HDACs are a class of enzymes that have a broad set of biochemical modifications and can affect DNA demethylation and synergy with other therapeutic agents. The final therapy includes using RNA-based approaches to enhance stability, specificity, and efficacy, especially in diseases that are caused by RNA alterations. Emerging concepts concerning the complexity and versatility of the epigenome may suggest ways to target genomewide cellular processes. Other studies suggest that eventual seminal regulator targets may be identified allowing with alterations to the massive epigenetic reprogramming during gametogenesis. Many future treatments may extend beyond being purely therapeutic and may be preventable perhaps in the form of a vaccine. Newer high throughput technologies when combined with advances in imaging modalities such as in vivo optical nanotechnologies may give rise to even greater knowledge of genomic architecture, nuclear organization, and the interplay between the immune and nervous systems. [21]

See also

Related Research Articles

<span class="mw-page-title-main">Demyelinating disease</span> Any neurological disease in which the myelin sheath of neurons is damaged

A demyelinating disease refers to any disease affecting the nervous system where the myelin sheath surrounding neurons is damaged. This damage disrupts the transmission of signals through the affected nerves, resulting in a decrease in their conduction ability. Consequently, this reduction in conduction can lead to deficiencies in sensation, movement, cognition, or other functions depending on the nerves affected.

Psychoneuroimmunology (PNI), also referred to as psychoendoneuroimmunology (PENI) or psychoneuroendocrinoimmunology (PNEI), is the study of the interaction between psychological processes and the nervous and immune systems of the human body. It is a subfield of psychosomatic medicine. PNI takes an interdisciplinary approach, incorporating psychology, neuroscience, immunology, physiology, genetics, pharmacology, molecular biology, psychiatry, behavioral medicine, infectious diseases, endocrinology, and rheumatology.

<span class="mw-page-title-main">Astrogliosis</span> Increase in astrocytes in response to brain injury

Astrogliosis is an abnormal increase in the number of astrocytes due to the destruction of nearby neurons from central nervous system (CNS) trauma, infection, ischemia, stroke, autoimmune responses or neurodegenerative disease. In healthy neural tissue, astrocytes play critical roles in energy provision, regulation of blood flow, homeostasis of extracellular fluid, homeostasis of ions and transmitters, regulation of synapse function and synaptic remodeling. Astrogliosis changes the molecular expression and morphology of astrocytes, in response to infection for example, in severe cases causing glial scar formation that may inhibit axon regeneration.

<span class="mw-page-title-main">Microglia</span> Glial cell located throughout the brain and spinal cord

Microglia are a type of glial cell located throughout the brain and spinal cord of the central nervous system (CNS). Microglia account for about 10–15% of cells found within the brain. As the resident macrophage cells, they act as the first and main form of active immune defense in the CNS. Microglia originate in the yolk sac under tightly regulated molecular conditions. These cells are distributed in large non-overlapping regions throughout the CNS. Microglia are key cells in overall brain maintenance – they are constantly scavenging the CNS for plaques, damaged or unnecessary neurons and synapses, and infectious agents. Since these processes must be efficient to prevent potentially fatal damage, microglia are extremely sensitive to even small pathological changes in the CNS. This sensitivity is achieved in part by the presence of unique potassium channels that respond to even small changes in extracellular potassium. Recent evidence shows that microglia are also key players in the sustainment of normal brain functions under healthy conditions. Microglia also constantly monitor neuronal functions through direct somatic contacts via their microglial processes, and exert neuroprotective effects when needed.

<span class="mw-page-title-main">Neuroimmune system</span>

The neuroimmune system is a system of structures and processes involving the biochemical and electrophysiological interactions between the nervous system and immune system which protect neurons from pathogens. It serves to protect neurons against disease by maintaining selectively permeable barriers, mediating neuroinflammation and wound healing in damaged neurons, and mobilizing host defenses against pathogens.

<span class="mw-page-title-main">CX3C motif chemokine receptor 1</span> Protein-coding gene in the species Homo sapiens

CX3C motif chemokine receptor 1 (CX3CR1), also known as the fractalkine receptor or G-protein coupled receptor 13 (GPR13), is a transmembrane protein of the G protein-coupled receptor 1 (GPCR1) family and the only known member of the CX3C chemokine receptor subfamily.

Neural tissue engineering is a specific sub-field of tissue engineering. Neural tissue engineering is primarily a search for strategies to eliminate inflammation and fibrosis upon implantation of foreign substances. Often foreign substances in the form of grafts and scaffolds are implanted to promote nerve regeneration and to repair damage caused to nerves of both the central nervous system (CNS) and peripheral nervous system (PNS) by an injury.

Protective autoimmunity is a condition in which cells of the adaptive immune system contribute to maintenance of the functional integrity of a tissue, or facilitate its repair following an insult. The term ‘protective autoimmunity’ was coined by Prof. Michal Schwartz of the Weizmann Institute of Science (Israel), whose pioneering studies were the first to demonstrate that autoimmune T lymphocytes can have a beneficial role in repair, following an injury to the central nervous system (CNS). Most of the studies on the phenomenon of protective autoimmunity were conducted in experimental settings of various CNS pathologies and thus reside within the scientific discipline of neuroimmunology.

Adult mesenchymal stem cells are being used by researchers in the fields of regenerative medicine and tissue engineering to artificially reconstruct human tissue which has been previously damaged. Mesenchymal stem cells are able to differentiate, or mature from a less specialized cell to a more specialized cell type, to replace damaged tissues in various organs.

<span class="mw-page-title-main">Gut–brain axis</span> Biochemical signaling between the gastrointestinal tract and the central nervous system

The gut–brain axis is the two-way biochemical signaling that takes place between the gastrointestinal tract and the central nervous system (CNS). The term "microbiota–gut–brain axis" highlights the role of gut microbiota in these biochemical signaling. Broadly defined, the gut–brain axis includes the central nervous system, neuroendocrine system, neuroimmune systems, the hypothalamic–pituitary–adrenal axis, sympathetic and parasympathetic arms of the autonomic nervous system, the enteric nervous system, vagus nerve, and the gut microbiota.

Neuroinflammation is inflammation of the nervous tissue. It may be initiated in response to a variety of cues, including infection, traumatic brain injury, toxic metabolites, or autoimmunity. In the central nervous system (CNS), including the brain and spinal cord, microglia are the resident innate immune cells that are activated in response to these cues. The CNS is typically an immunologically privileged site because peripheral immune cells are generally blocked by the blood–brain barrier (BBB), a specialized structure composed of astrocytes and endothelial cells. However, circulating peripheral immune cells may surpass a compromised BBB and encounter neurons and glial cells expressing major histocompatibility complex molecules, perpetuating the immune response. Although the response is initiated to protect the central nervous system from the infectious agent, the effect may be toxic and widespread inflammation as well as further migration of leukocytes through the blood–brain barrier may occur.

Jaime Imitola is an American neuroscientist, neurologist and immunologist. Imitola's clinical and research program focuses on Progressive Multiple Sclerosis and the molecular and cellular mechanisms of neurodegeneration and repair in humans. His research includes the translational neuroscience of neural stem cells into patients. Imitola is known for his discoveries on the intrinsic immunology of neural stem cells, the impact of inflammation in the endogenous neural stem cell in multiple sclerosis, and the ethical implications of stem cell tourism in neurological diseases.

Microglia are the primary immune cells of the central nervous system, similar to peripheral macrophages. They respond to pathogens and injury by changing morphology and migrating to the site of infection/injury, where they destroy pathogens and remove damaged cells.

Otilimab is a fully human antibody which has been developed by the biotechnology company MorphoSys. It can also be referred to as HuCAL antibody, HuCAL standing for Human Combinatorial Antibody Library and being a technology used to generate monoclonal antibodies. Otilimab is directed against the granulocyte-macrophage colony stimulating factor (GM-CSF), a monomeric glycoprotein functioning as a cytokine promoting both proliferation and activation of macrophages and neutrophils.

<span class="mw-page-title-main">Michal Schwartz</span> Professor of neuroimmunology

Michal Schwartz is a professor of neuroimmunology at the Weizmann Institute of Science. She is active in the field of neurodegenerative diseases, particularly utilizing the immune system to help the brain fight terminal neurodegenerative brain diseases, such as Alzheimer's disease and dementia.

<span class="mw-page-title-main">Robyn S. Klein</span> American neuroimmunologist

Robyn S. Klein is an American neuroimmunologist as well as the Vice Provost and Associate Dean for Graduate Education at Washington University in St. Louis. Klein is also a professor in the Departments of Medicine, Anatomy & Neurobiology, and Pathology & Immunology. Her research explores the pathogenesis of neuroinflammation in the central nervous system by probing how immune signalling molecules regulate blood brain barrier permeability. Klein is also a fervent advocate for gender equity in STEM, publishing mechanisms to improve gender equity in speakers at conferences, participating nationally on gender equity discussion panels, and through service as the president of the Academic Women’s Network at the Washington University School of Medicine.

<span class="mw-page-title-main">Katerina Akassoglou</span> Greek neuroimmunologist

Katerina Akassoglou is a neuroimmunologist who is a Senior Investigator and Director of In Vivo Imaging Research at the Gladstone Institutes. Akassoglou holds faculty positions as a Professor of Neurology at the University of California, San Francisco. Akassoglou has pioneered investigations of blood-brain barrier integrity and development of neurological diseases. She found that compromised blood-brain barrier integrity leads to fibrinogen leakage into the brain inducing neurodegeneration. Akassoglou is internationally recognized for her scientific discoveries.

Helga (Elga) De Vries is a Dutch neuroimmunologist and a Full Professor in the Department of Molecular Cell Biology and Immunology at Amsterdam University Medical Centers in Amsterdam, The Netherlands. De Vries is a leader in the field of blood brain barrier research. She founded the Dutch Blood Brain Barrier Network and is the President of the International Brain Barrier Society. De Vries’ research explores the interactions between the brain and the immune system and she specifically looks at neurovascular biology in the context of neurodegenerative diseases such as multiple sclerosis and Alzheimer's disease.

Malú G. Tansey is an American Physiologist and Neuroscientist as well as the Director of the Center for Translational Research in Neurodegenerative Disease at the University of Florida. Tansey holds the titles of Evelyn F. and William L. McKnight Brain Investigator and Norman Fixel Institute for Neurological Diseases Investigator. As the principal investigator of the Tansey Lab, Tansey guides a research program centered around investigating the role of neuroimmune interactions in the development and progression of neurodegenerative and neuropsychiatric disease. Tansey's work is primarily focused on exploring the cellular and molecular basis of peripheral and central inflammation in the pathology of age-related neurodegenerative diseases like Alzheimer's disease and amyotrophic lateral sclerosis.

Epigenetics of autoimmune disorders is the role that epigenetics play in autoimmune diseases. Autoimmune disorders are a diverse class of diseases that share a common origin. These diseases originate when the immune system becomes dysregulated and mistakenly attacks healthy tissue rather than foreign invaders. These diseases are classified as either local or systemic based upon whether they affect a single body system or if they cause systemic damage.

References

  1. ↑ Functional Links between the Immune System, Brain Function and Behavior
  2. ↑ Kipnis J, Derecki NC, Yang C, Scrable H (October 2008). "Immunity and cognition: what do age-related dementia, HIV-dementia and 'chemo-brain' have in common?". Trends Immunol. 29 (10): 455–63. doi:10.1016/j.it.2008.07.007. PMID   18789764.
  3. ↑ Abdolmaleky H.M.; Thiagalingam S.; Wilcox M. (2005). "Genetics and epigenetics in major psychiatric disorders: dilemmas, achievements, applications, and future scope". American Journal of Pharmacogenomics. 5 (3): 149–160. doi:10.2165/00129785-200505030-00002. PMID   15952869. S2CID   16397510.
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  9. ↑ Abel T.; Zukin R.S. (2008). "Epigenetic targets of HDAC inhibition in neurodegenerative and psychiatric disorders". Current Opinion in Pharmacology. 8 (1): 57–64. doi:10.1016/j.coph.2007.12.002. PMC   2405764 . PMID   18206423.
  10. ↑ Pandey U.B.; Nie Z.; Batlevi Y.; McCray B.A.; Ritson G.P.; Nedelsky N.B.; Schwartz S.L.; DiProspero N.A.; Knight M.A.; et al. (2007). "HDAC6 rescues neurodegeneration and provides an essential link between autophagy and the UPS". Nature. 447 (7146): 859–863. Bibcode:2007Natur.447..860P. doi:10.1038/nature05853. PMID   17568747. S2CID   4365061.
  11. ↑ Ballas N.; Mandel G. (2005). "The many faces of REST oversee epigenetic programming of neuronal genes". Current Opinion in Neurobiology. 15 (5): 500–506. doi:10.1016/j.conb.2005.08.015. PMID   16150588. S2CID   32596790.
  12. ↑ Bailey, S.L., Carpentier, P.A., McMahon, E.J., Begolka, W.S., Miller, S.D., 2006. Innate and adaptive immune responses of the central nervous system. Critical Reviews in Immunology. 26, 149–188.
  13. ↑ Hauser S.L.; Oksenberg J.R. (2006). "The neurobiology of multiple sclerosis: genes, inflammation, and neurodegeneration". Neuron. 52 (1): 61–76. doi: 10.1016/j.neuron.2006.09.011 . PMID   17015227.
  14. ↑ Sawalha A.H. (2008). "Epigenetics and T-cell immunity". Autoimmunity. 41 (4): 245–252. doi:10.1080/08916930802024145. PMID   18432405. S2CID   46300553.
  15. ↑ Gray, S.G., Dangond, F., 2006. Rationale for the use of histone deacetylase inhibitors as a dual therapeutic modality in multiple sclerosis. Epigenetics 1, 67–75.
  16. ↑ "WHAT IS ME?". MEAction. Retrieved 21 August 2018.
  17. ↑ Bonomi, Robin; Hillmer, Ansel T.; Woodcock, Eric; Bhatt, Shivani; Rusowicz, Aleksandra; Angarita, Gustavo A.; Carson, Richard E.; Davis, Margaret T.; Esterlis, Irina; Nabulsi, Nabeel; Huang, Yiyun; Krystal, John H.; Pietrzak, Robert H.; Cosgrove, Kelly P. (2024-08-27). "Microglia-mediated neuroimmune suppression in PTSD is associated with anhedonia". Proceedings of the National Academy of Sciences. 121 (35). doi:10.1073/pnas.2406005121. ISSN   0027-8424.
  18. ↑ Oke S.L.; Tracey K.J. (2008). "From CNI-1493 to the immunological homunculus: physiology of the inflammatory reflex". Journal of Leukocyte Biology. 83 (3): 512–517. doi:10.1189/jlb.0607363. PMID   18065685. S2CID   612157.
  19. ↑ Gold, Stefan M, Irwin, Michael R, 2009. Depression and Immunity: Inflammation and Depressive Symptoms in Multiple Sclerosis. 29, 309.
  20. ↑ Gaikwad, Sagar; Agrawal-Rajput, Reena (2015-01-01). "Lipopolysaccharide from Rhodobacter sphaeroides Attenuates Microglia-Mediated Inflammation and Phagocytosis and Directs Regulatory T Cell Response". International Journal of Inflammation. 2015: 361326. doi: 10.1155/2015/361326 . ISSN   2090-8040. PMC   4589630 . PMID   26457222.
  21. ↑ Rauch J.; Knoch T.A.; Solovei I.; Teller K.; Stein S.; Buiting K.; Horsthemke B.; Langowski J.; Cremer T.; et al. (2008). "Light optical precision measurements of the active and inactive Prader–Willi syndrome imprinted regions in human cell nuclei". Differentiation. 76 (1): 66–82. doi:10.1111/j.1432-0436.2007.00237.x. PMID   18039333.

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