Hematopoiesis is the development of immune and other blood cells from a small population of stem cells known as hematopoietic stem cells (HSCs). In the embryo, hematopoiesis takes place within the yolk sac, in special tissue called blood islands . Later in development, the spleen, liver, and lymphoid tissues take over this responsibility. As the Bone Marrow (BM) develops and becomes functional, it becomes the main site of blood and immune cell formation. In children, hematopoiesis occurs in the medullary cavity of long bones such as the tibia. In contrast, within the adult, the major site of hematopoiesis is the BM of irregular bones such as the pelvis, cranium, vertebrae and sternum . Yet, the maturation and activations of these cells occurs throughout the body, either in secondary lymphoid organs or the blood itself.
The human nervous system exerts great influence on the homeostasis of the body; this includes regulation of bone marrow processes like hematopoiesis. Tachykinins are small neuropeptides from 10-12 amino acids long synthesized in various nuclei of the central nervous system such as the substania gelatinosa of the dorsal spinal cord and certain nuclei of the limbic lobes as well as in a number of non-neuronal tissues like stromal cells of the BM . Within the bone marrow, the tachykinins have been shown to have critical effects on the microenvironment, including metastasis and dormancy of cancer cells during clinical remission.
In this chapter we attempt to uncover the different roles of tachykinins in human disease and homeostatic conditions, in particular hematopoiesis within the bone marrow cavity. We also discuss normal synthesis of tachykinins and their receptors, yet focus on their regulation by microRNA, messenger RNA stabilizing proteins, and transcription factors like Restrictive Element-1 Silencing Factor (REST). We discuss the consequence of the tachykinins to pathological conditions such as breast cancer development. We also review the normal processes during their role as neurotransmitters.
Hematopoietic Stem Cell (HSC) Differentiation
HSCs are pluripotent, self-renewing stem cells of the marrow cavity. HSCs have multiple lineages of differentiation to produce myeloid and lymphoid progenitors and mature cells . Lymphoid cells are among the white blood cell population that are generated from HSCs into pro-T and pro-B cells, which later reach maturation in the thymus and BM, respectively. Myeloid cells include any leukocytes that are not lymphocytes such as eosinophils, basophils and neutrophils, these mature peripherally. When a HSC divides, one daughter cell proceeds to differentiate into immune or red blood cells while the other daughter cell is preserved as a HCS through the process of self-renewal . The process by which the daughter cell differentiates is highly regulated by extracellular signals, which as cytokines and paracrine factors pertaining to the bone marrow microenvironment. Hematopoietic regulators can be produced by osteoblasts, stroma, and Mesenchymal Stem Cells (MSCs).
Erythropoietin (EPO), a glycoprotein is produced by the peritubular capillary endothelial cells of the kidneys to stimulate erythropoiesis . A number of other cytokines have been associated to tachykinin-mediated regulation of hematopoiesis, among these are: IL-1, IL-3, IL-6, IL-11 . Tachykinins can also lead to increases in the production of the pro-inflammatory cytokine tumor necrosis factor-alpha (TNF-alpha), inhibitory factors such as macrophage inflammatory protein-1alpha (MIP-1alpha) and transforming growth factor-beta (TGF-beta) [8-10].
MSCs and Bone Marrow Function
MSCs are multipotent stem cells that can differentiate into a variety of mesodermal cell types, including osteoblasts, chondrocytes, myocytes, adipocytes, and even into beta-pancreatic islet cells . Subsequent experimentation has revealed the immense plasticity of these BM cells and how their fate could be determined by environmental factors . MSCs also have a large capacity for self-renewal while maintaining their multipotency.
MSCs have become of great interest for clinical use because of their immunosuppressive properties. The implications of MSC-induced immunosuppression are very broad in the context of therapy. For instance, the immunosuppressive effects of MSCs can be used to inhibit chronic inflammatory stress and promote tolerance in an allogeneic setting . Their effects are partly mediated through the release of soluble factors and secondary effects on immune cells, such as T cells, B cells and dendritic cells . Their immunosuppressive function allows allogeneic MSCs to be transplanted without the risk of rejection.
MSCs and HSCs maintain a very interesting relationship with regards to the microenvironment and development of one another. HSCs can stimulate the differentiation of MCS through the osteogenic pathway and end with the formation of osteoblasts . The synthesis of Bone Morphogenic Proteins 2 (BMP2) and 6 (BMP6) are responsible for this osteoblastic lineage induction. When animal models were exposed to stress, as defined by bleeding, this effect was even greater. On the other hand, osteoblasts have been shown to enhance the hematopoietic process and mobilization . In ATM deficient mice, the osteoblastic support of HSCs is not present, thus implicating ATM as a mediator or intermediate. Also, since ATM is activated by DNA damage, this shows how DNA damage in one cells type can lead to the expansion of the other, in this case the HSC population.
Neural Regulation of Hematopoiesis
Neuropeptides and neurotransmitters have a profound effect on HSC differentiation. Psychophysiological conditions such as stress and anxiety have been shown to alter the functioning of the hematopoietic process . Also, illicit drug usage as well as psychopathology has profound effects on normal bone marrow functioning . Thus it is no surprise that cell populations of the BM can express receptors to a number of neurotransmitters and mediate their effects within the marrow microenvironment.
Neurotrophins are a family of proteins better known for their ability to mediate neuronal differentiation and normal processes . Neurotrophins bind to tyrosine kinase receptors known as TrK receptors. The experimental evidence indicates that neurotrophins can have an effect on colony formation and development of the immune system . Neurotrophic factors like Nerve Growth Factor (NGF) can act synergistically with cytokines in cellular maturation. This was demonstrated in studies with IL-2 in B-lymphocytes; here IL-2 and NGF increased the expression of the other receptors . Basophilic cell differentiation also shows a synergistic response of NGF with GM-CSF . NGF, NT-2 and TrK are expressed in leukemia cell lines, underscoring the relevance of neurotrophins as autocrine mediators in the development of this hematological malignancy .
The gaseous neurotransmitter Nitric Oxide (NO) plays a number of important roles in local neural modulation of central and peripheral processes such as vasodilatation. NO is synthesized by Nitric Oxide Synthase (NOS) and the receptor for NO is the intracellular soluble guanylyl cyclase (sGC). In bone marrow, NO negatively regulates hematopoiesis and differentiation .
Thus, inhibition of NOS leads to greater numbers of HSCs and progenitor cells within the BM. NOS has three variants within the human genome, inducible NOS (iNOS), endothelial NOS (eNOS) and Neuronal NOS (nNOS). Stromal cells are of great interest because they have been show to synthesize a number of neurotransmitters and express receptors for other neurotransmitters, thus presenting a pathway for the neural/hematopoietic axis . Stromal cells of the BM have been shown to express nNOS; thus present NO has a paracrine regulator of hematopoiesis within the cavity. Knockdown of nNOS within stromal cells shows an increase in hematopoietic capacity of the BM . This shows that neural regulation of hematopoiesis can take place within the microenvironment of the bone marrow.
Unlike Nitric Oxide, Melatonin has shown to stimulate the formation of hematopoietic progenitors . In addition, Melatonin is able to assist myeloid progenitors avoid apoptosis and cellular death by chemotherapeutic drugs. The actions of this neurotransmitter seem to be related to its ability to induce the production of opioids, Melatonin-Induced Opioids (MIO). Yet, the receptor to MIO is found on bone marrow stromal cells. Competition and binding assays has determined that the kappa-Opioid receptor expressed by stroma is the main mediator of MIO in hematopoiesis .
The tachykinins comprise a very large family of neuropeptides expressed in a wide range of animals from reptiles to mammals . Tachykinins are characterized by the conservation of a carboxy terminal sequence FXGLM-NH2. Within this family are Substance P, Neurokinin A, Neuropeptide K, Neuropeptide -γ, and Neurokinin B. In humans, three genes encode tachykinin precursors, preprotachykinins. TAC1, TAC3, TAC4 are the human homolog genes and are found on chromosome 7, 12, and 17 respectively. These are also known as preprotachykinin-A (PPT-A), PPT-B and PPT-C.
The TAC1 gene encodes the majority of the tachykinins by alternative splicing and post-translational modifications. The TAC1 has 7 exons and allows for transcription of Substance P, Neurokinin A, Neuropeptide K and Neuropeptide -γ. Substance P, also known as neurokinin 1 is an 11-amino acid peptide. The TAC3 gene is similar in structure to the TAC1 gene in that both contain 7 exons spaced by 6 introns. Yet, the TAC3 gene only produces Neurokinin B. The latest member of the family TAC4 encodes for hemokinin-1 (HK-1), and Endokinins A-D (EKA, EKB, EKC, and EKD) .
Most of the tachykinins are deca or undecapeptides. In addition, post-translational variants of these exist such as the substance P 1-4, a four amino acid peptide shown to negatively regulate hematopoiesis . Tachykinins are expressed in neuronal and non-neuronal tissues such as BM and mature blood cells. As a matter of fact, the TAC4 gene is mostly expressed in tissues on non-ectodermal origin . Most of the effects of Tachykinins are mediated via their Neurokinin receptors.
Substance P and NK1
In the Nervous System, specifically the central nervous system, substance P has been correlated with a number of physiological conditions including depression, anxiety, stress, pain and neurogenesis . Much like the other Tachykinins, Substance P also has profound effects on the gastrointestinal tract, where it modulates enteric motor activity and the reabsorption/secretion of fluids and ions .
The preferred receptor for Substance P is the neurokinin 1 receptor (NK1), which belongs to a subfamily of G-protein coupled receptors. NK1 signaling leads to the activation of phospholipase C (PLC) and then inositol triphosphate (IP3); leading to calcium release from storage within the endoplasmic reticulum . NK1 is the final product of transcription of the TACR1 gene located on chromosome two in humans and six in mice .
Substance P has been the most studied tachykinin because it is used as a model in most of the reports pertaining to immune-mediated functions by this family of peptides. Substance P is involved in inflammatory responses: stimulation of lymphocytes and regulation of tissue repair, enhancement of phagocytosis, chemotaxis and release of histamine, induction of mast cell degranulation, enhancement of immunoglobulin production and functions as a terminal differentiation cofactor for B cells [37-44]. Substance P induces cytokine production in immune and hematopoietic cells. These include interleukin (IL) -1, IL-2, IL-3, IL-6, TNF-alpha, granulocyte-macrophage colony-stimulating factor (GM-CSF), and interferon gamma .
Neurokinin A and NK2
Neurokinin A, also known as Substance K, is similar in structure and function to Substance P. Neurokinin-A is a decapeptide neurotransmitter and its functions are mediated by the Neurokinin-2 (NK2) receptor. NK2 is also a G-protein coupled receptor. Neurokinin A has the ability to constrict smooth muscles and dilate blood vessels of the airways and gastrointestinal tract .
In a seemingly contradictory manner, Substance P enhances the proliferation of myeloid progenitors whereas neurokinin A significantly inhibits their proliferation; yet substance P and neurokinin-A stimulate the early and late erythroid progenitors . These results suggest that the hematopoietic effects exerted by neurokinin-A depend on the particular committed progenitor, as indicated by its stimulation on erythroid progenitors and its inhibition on granuloytic progenitors. If cultured in the absence of stromal cells, neither effect is observed, thus, indicating a possible role for stromal cells in NK-A actions.
Neurokinin-A, much like Substance P, has the ability to stimulate the production and secretion of cytokines with hematopoietic regulatory effect. Stimulation of stromal cells with neurokinin-A resulted in the production of MIP-1alpha and TGF-beta proteins . Together these studies indicate that local production of cytokines and tachykinins by bone marrow cells such as stromal cells results in a tight regulation of hematopoiesis and function.
Neurokinin B and NK3
Neurokinin B is a decapepide tachykinin and the sole product of the TAC3 gene. Although all tachykinins are able to bind to the Tachykinin receptors with varying affinities, Neurokinin-B binds preferably to the NK-3 receptor. Recently, Klassert et al., confirmed expression of neurokinin-B in some immune cell populations. mRNA for NK-B was detected in lymphocytes and monocytes, yet the NK3 receptor was not detected. The function of neurokinin-B in these cells is still undefined .
The main known action of neurokinin-B seem to be linked to reproduction. Neurokinin-B expression had been found clearly in the arcuate nucleus of the hypothalamus with a gender difference in expression, the female population having greater numbers of neurokinin-B expressing neurons . These neurons are highly responsive to estrogen. Due to the close proximity of the Gonadotropin Releasing Hormone (GnRH) producing neurons, it is postulated that neurokinin-B may regulate these and coordinate the neuroendocrine system. Neurokinin-B is also highly expressed by the placenta of pregnant women during term and preterm labor as opposed to cesarean section births , thus implicating neurokinin-B in the birthing process.
Postmenopausal women have a greater number of neurokinin-B-expressing neurons in the arcuate nucleus . Using ovariectomized rats, Rance et. al. showed that neurons of the arcuate nucleus are modulated by hormones of the ovaries and that the increase in expression of post-menopausal women is because of ovarian failure the accompanies this phase.
TAC1 and Human Disease
TAC1 expression has been associated to a number of different cancers and autoimmune disorders. In colon cancer, the cancerous cells utilize substance P as an autocrine factor, based on the outcome of a specific NK1 antagonist . Yet, it appears that Substance P can also accelerate the immune response against the cancer cells by increased proliferation of killer cells . With respect to gastric adenocarcinoma and esophageal carcinoma, it has been shown that the TAC1 promoter undergoes high levels of methylation, which has been suggested to be linked to poor prognosis in patients .
Multiple Sclerosis (MS) is an inflammatory disease caused by an autoimmune disorder affecting the Central Nervous System (CNS) leading to a myriad of nervous sensory and motor deficiencies. In familial studies certain genomic regions have become of great interest. One of these is chromosome 7q21-22. It has been determined that the close proximity of this region to the TAC1 gene leads to greater predisposition . Substance P plays a role in CNS inflammation through the induction of interleukin secretion by astrocytes . Thus, it has been inferred that the etiology of the inflammation seen in MS patients may be due to aberrant local production of Substance P in by mutations of this genomic region.
Narcolepsy is a condition with genetic predisposition in which the patient succumbs to sudden attacks of sleep throughout the day, lasting around fifteen minutes. Sleep paralysis and dream-like hallucinations are also common with this neurological disorder. It is believed that the etiology of this condition is a sudden decrease or lack of production of a protein pair called Hypocretins or Orexins . This decrease may be the result of an autoimmune reaction against the Orexin producing cells of the hypothalamus. Substance P has also been associated to narcolepsy. CSF samples from narcoleptic patients have revealed a marked decrease in Substance P levels . In addition, the FDA currently approved treatment for narcolepsy is methamphetamines such as methylphenidate, which have shown to increase the lowered level of endogenous substance P.
TAC1 promotes breast cancer dormancy within the Bone Marrow
TAC1 has been implicated in the pathology of breast cancer. TAC1 expression favors invasion and dormancy of the Breast Cancer Cells (BCC) within the Bone Marrow . BCC express both NK1 and NK2 receptors that mediate cellular proliferation through autocrine signaling. Within the Bone Marrow, BCC encounter a microenvironment that supports proliferation while providing protection from first line treatments like chemotherapy.
Using a co-culture approach to mimic early bone marrow invasion by BCC, Rao et. al. showed that stromal and BCC grow as a monolayer without foci, but contact inhibition of growth, which shows reversion of the behavior of BCCs. During this period of quiescence, both stromal and BCC were viable for up to four months, whereas, BCC alone reached confluence, established foci, and underwent death after two months. Also, the co-cultured cells reached confluence in about half the normal time. It was determined that BCCs did not interfere with the normal hematopoietic process.
BCCs in which the TAC1 gene is stably suppressed by small interfering RNA (siRNA) lack the ability to form co-cultures with stromal cells and exhibit the properties previously mentioned. Non-tumorogenic cell lines in which TAC1 is over-expressed showed oncogenic properties, thus implicating this gene in cell transformation. This was validated with human primary samples. Also, in nude mice, BCCs with TAC1 silenced could not invade the marrow cavity, unlike their TAC1-expressing equivalents. Thus, TAC1 and substance P production plays an important role in the transformation of BCCs and allows for their integration within the bone marrow cavity. This provides evidence that novel therapies can be developed to interrupt this mechanism in an effort to eradicate malignant cells in patients.
mRNA Stabilizing proteins and MicroRNA modulation of TAC1
In adults, the bone marrow is the major site of hematopoiesis. Within this cavity exists three important cellular components, HSCs, MSCs and Stromal cells. Stroma produces a number of important hematopoietic regulators, including neurotransmitters, cytokines and chemokines. Since stroma also expresses a number of receptors for neurotransmitters and neuropeptides, they provide a pathway for neural regulation of hematopoiesis. NK1, the substance P receptor requires induction by cytokines in stroma for its expression; whereas NK2 is constitutively expressed .
As discussed above, binding of substance P to NK1 receptor results in stimulation of hematopoiesis; whereas and neurokinin-A exhibits suppressive effects through the NK2 receptor. Also, Stem Cell Factor (SCF) and IL-11 have been associated with simulation of hematopoiesis . In contrast, TGF-beta inhibits hematopoiesis and immunological activation. NK-A has been shown to increase the expression of TGF-beta1 in stromal cells. Through gel shift analysis, Murthy et al., showed that cytokine stimulated stromal cells expressed mRNA binding proteins, which stabilized TAC1 expression .
MicroRNAs are emerging as key players when discussing cell biology. They are post-transcriptional regulators of protein expression. They range from 19-23 nucleotides and are non-coding RNA molecules. To exert their effect, miRNA bind to the 3’ Untranslated Region (UTR) of their target mRNA to suppress the translation of the transcript. With regards to the TAC1 transcript, mir-130a, -206, and to a letter extent, -302a, have been validated for TAC1. Murthy et al., showed that in stromal cells, once stimulated with IL-11, SCF or TGF-beta, mir-130a decreased and mir-302a increased as compared to control samples. mir-206 showed no significant change in expression with any cytokine stimulation. Anti-miR to 130a resulted in over 8000-fold activation of the gene with the 3ʹ UTR of TAC1.
Although Mesenchymal Stem Cells (MSCs), at times, have been designated as cells of mesodermal origin, they can be transdifferentiated into cells of ectodermal origin, specifically into dopamine-producing neurons . To do so, the use of rodent neuronal conditioned media, gene transfection or chemical inducers is necessary. In these MSC-derived neuronal cells, TAC1 is expressed, yet protein levels were kept moderately low. After stimulation with IL-1alpha, TAC1 mRNA is translated to substance P. Greco et al., showed that IL-1alpha induces TAC1 translation though its negative effect on microRNA expression. After several analyses, mir-130a and -206 were shown to be responsible for the suppression of TAC1 translation in the MSC- derived neurons. Since IL-1alpha is a proinflammatory mediator, this shows the influence an inflammatory environment can have on the expression of neurotransmitters like Substance P .
Restrictive Element-1 Silencing Transcription Factor (REST) regulation of Tachykinins
Restrictive Element-1 Silencing Transcription Factor (REST) regulation of Tachykinins
REST, also known as the neural restrictive selecting factor (NRSF) or Neuron Restrictive Silencing Factor (NRSF) is a transcription factor that has emerged as a key player in neural development. It is believed that the main function of REST is to silence the expression of mature neuron-specific genes in non-neuronal cells and neuronal progenitors . REST blocks transcription by binding a consensus 21 bp RE-1 site (NRSE) present on target genes regulatory elements. Gene repression occurs by binding of REST to the NRSE motif and through the assembly of multiple co-factors on its amino and carboxyl terminal. Regulation of transcription occurs through histone deacetylation, chromatin remodeling and methylation. Interestingly, REST has also been linked to tumor suppresser activities and oncogenic activities, further implicating the role of REST in development .
REST negatively regulates TAC1 expression and its loss in breast cancer appears to be involved in the aggressiveness of cancer. Reddy et al., showed that less aggressive cancer cell lines showed higher expression of REST and the inverse was seen in highly aggressive breast cancer cell lines like MDA-MB-231 cells. In addition, REST over-expression reduced cell proliferation, where REST knockdown by siRNA (small interfering RNA) increased cell proliferation. The results with cell lines were validated in human primary cancer samples. Taken together, these results showed that REST may play a role in the oncogenic properties of TAC1 in breast cancer cells .
Recently, REST has also been shown to enhance the expression of the TAC3 or Neurokinin B gene. Neurokinin B is associated to temporal epilepsy as a proepileptic agent. Gillies et. al. uncovered a putative REST/NRSF binding site on the TAC3 gene at +50-71, there was great degree of homology with other genes known to be regulated by REST/NRSF, such as voltage-gated sodium channels (NaV) and Synapsin. They found that over-expression of REST led to an increase in TAC3 mRNA molecules as measured by RT-PCR. Utilizing human neuroblastoma cells as a model, treatment with the anticonvulsant, Carpamazepine, expression of REST decreased and subsequently, so did Neurokinin B levels. This shows that REST regulation of the tachykinins is tissue-specific. In other cases, REST negatively regulate the expression of TAC1, such as in breast cancer cells, and in others it has an enhancing ability like in hippocampal regions of the brain. In either case, aberrant expression is associated to a critical disease, epilepsy and malignant cancer .
REST also has a neuron-specific, truncated isoform known as sREST or REST4. This shorter variation has only five of the eight zinc fingers and lacks the repression domain located in the REST C -Terminus. Although many different roles have been postulated for REST4, it has been strongly suggested to mainly act as an antagonist to the full form REST protein, although there is also some evidence that REST4 can retain the inhibitory effects of its full-length precursor .
Tabuchi et al., showed that REST can repress the expression of Brain Derived Neurotrophic Factor (BDNF) in cortical neurons. REST4 alone showed weak inhibitory effects . Yet, when both REST and REST4 were expressed, REST4 antagonized REST induced repression, thus allowing expression of the neuronal gene product in these cortical neurons. On the other hand, Palm et al., showed in rat glioma cell lines, the truncated version of REST, REST4, could repress BDNF expression as determined by a construct activity with the BDNF promoter. It is believed that REST4 may maintain repressive abilities because of a N-terminus repressor domain that is conserved in both the truncated and full-length proteins.
After discussion of the Tachykinin family and its receptors, with relation to their hematological effects, one understands how the nervous system can affect the generation of blood components and immune cells. In addition, it is clear that the regulation of the tachykinins involves a complex mechanism and that dysregulation at any phase along the pathway can be pathological. The tachykinins represent a large and complex family with members be discovered as science progresses. They provide an important link between both the central nervous system and the bone marrow niche. Yet, endogenous expression by bone marrow components shows how tachykinins can mediate local effects through stromal cells without the need for neuronal input. Tachykinins also play an important role outside of the BM such as in the development of other diseases like cancer and autoimmune conditions.
This work was supported by the FM Kirby Foundation.
JL Munoz, P Rameshwar – Department of Medicine Hematology/Oncology, University of Medicine and Dentistry of New Jersey, New Jersey Medical School, Newark, NJ 07103, USA
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