シンポジウム
48 神経と骨髄疾患の新たな展開
48 Emerging roles of nerve fibers in bone marrow disease
座長：檜山 武史（岡山大学学術研究院医歯薬学域）・片山 義雄（神戸大学 医学部附属病院） |
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| 2022年7月2日 14:00～14:24 ラグナガーデンホテル 羽衣：西 第10会場
3S10a-01
神経ー骨代謝ー造血システムネットワークによる骨髄機能制御
Bone marrow regulation by brain-bone-blood “3B” integration
*片山 義雄(1)
1. 神戸大学医学部附属病院
*Yoshio Katayama(1)
1. Kobe University Hospital
Keyword: bone marrow, bone, sympathetic nervous system
The hematopoietic organ, bone marrow (BM), is located inside the bone, and the hematopoietic and skeletal tissues contact directly in the endosteal region. We have studied for the past 20 years the intimate functional interaction between these systems which are governed by the sympathetic nervous system (SNS) in diverse ways. In particular, the egress of immature hematopoietic cells from BM to circulation is tightly controlled by brain-bone-blood “3B” integration which is practically utilized in the clinical hematology scene in the hospital. The signaling relay of this network is mediated by varied factors, e.g. cytokines, chemokines, hormones, neurotransmitters, lipid mediators, adhesion molecules together with wide variety of cellular constituents differentiated from two different stem cells, hematopoietic stem cells and mesenchymal stem cells. Neuronal regulation of bone/BM will be introduced and its usefulness for the research of BM diseases will be discussed. | | 2022年7月2日 14:24～14:48 ラグナガーデンホテル 羽衣：西 第10会場
3S10a-02
骨髄微小環境における正常および悪性造血の神経制御機構
Neural regulation of normal and malignant hematopoiesis in bone marrow microenvironment
*淺田 騰(1)
1. 岡山大学病院
*Noboru Asada(1)
1. Okayama University Hospital
Keyword: hematopoietic stem cell, niche , nervous system, malignant hematopoietic disease
Hematopoietic stem cells (HSCs), the ancestors of all blood cells, reside in a specialized microenvironment, the hematopoietic stem cell niche (niche), in the bone marrow under steady-state conditions. It is known that HSCs require extrinsic signals from the niche to exert their stem cell abilities, such as self-renewal, differentiation, and proliferation. Recent studies have identified various cell types that exist both inside and outside the bone marrow as niche constituents. Osteoblasts, located at the boundary between bone marrow and bone tissue and are responsible for osteogenesis and mesenchymal cells located around blood vessels in the bone marrow have been reported to function as niche cells. Recent advances in research based on the refinement of experimental methods have revealed the linkage mechanisms between the nervous system and the blood system, a relationship that at first glance may seem tenuous. Bone and bone marrow is abundantly innervated by the autonomic nerves and autonomic nervous signals have been shown to be involved in the regulation of hematopoiesis and the pathogenesis of hematopoietic malignancies such as leukemia. Adrenergic signals alter HSC niche function through beta-adrenergic receptors and regulate HSC migration, quiescence, and senescence. Robust catecholaminergic signals released by sympathetic nerve in the bone marrow stimulated by exogenous cytokine administration suppress function of osteoblasts at endosteum and osteocytes embedded in the mineralized bone, leading to the HSC egress from bone marrow into blood circulation. In old mice, the loss of adrenergic nerve fibers in BM was observed along with HSC aging. Strikingly, supplementation of sympathomimetric to old mice rejuvenated the function of aged HSCs. Proliferated leukemic cells have been shown to modify the bone marrow microenvironment to favor their survival by disrupting sympathetic nerve fibers in the bone marrow. In this presentation, we introduce the latest findings on the complex hematopoietic regulation by the nervous system, and the intriguing roles of the nervous system in malignant hematopoietic diseases will be discussed. | | 2022年7月2日 14:48～15:12 ラグナガーデンホテル 羽衣：西 第10会場
3S10a-03
骨髄腫-骨連関と痛み
Myeloma-bone interaction and pain
*安倍 正博(1)
1. 徳島大学大学院医歯薬学研究部
*Masahiro Abe(1)
1. Tokushima Univ Grad Sch, Tokushima, Japan
Keyword: bone marrow, multiple myeloma , acid, sensory neuron
Multiple myeloma (MM), a malignancy of plasma cells, is characterized by preferential accumulation of tumor cells in bone marrow and devastating bone destruction. MM frequently arises in elderly populations and its incidence has been rapidly increasing in the era of longevity. Despite recent great strides achieved in MM treatment owing to the implementation of new anti-MM agents, pain associated with its tumor progression and bone destruction remains a leading cause for deterioration in quality of life in patients with MM. Bone provides a unique microenvironment for MM cell growth and survival, including niches to foster clonogenic MM cells. MM cells stimulate bone resorption while suppressing bone formation to cause bone destruction, which in turn favors tumor growth, thereby forming a vicious cycle between tumor progression and bone destruction. MM cells, osteoclasts and osteocytes are all acid-producing cells to create an acidic milieu in bone. Sensory neurons were found to extend their axons in acidic culture conditions as well as in MM lesions in mouse models with up-regulation of pERK1/2 and pCREB, indicators for neuron excitation and pain, in their dorsal root ganglia. Interestingly, dendritic processes of osteocytes were in a physical contact via Cx43 gap junctions with CGRP+ sensory neuron fibers in the bone matrix to elicit sensory neuron excitation. A new insight into the underlying pathogenesis and possible directions of future treatment for pain associated with bone disease and tumor expansion will be presented. | | 2022年7月2日 15:12～15:36 ラグナガーデンホテル 羽衣：西 第10会場
3S10a-04
集積化神経プローブ開発と骨髄神経記録への展開
Multifunctional neural probes and their application to bone marrow
*田中 徹(1)
1. 東北大学大学院医工学研究科
*Tetsu Tanaka(1)
1. Grad Sch Biomed Eng, Tohoku Univ, Sendai, Japan
Keyword: Neural probe, Neural recording, Optical stimulation
Recently, many researchers have been developing biomedical devices for brain diseases, analyzing brain functions, and realizing brain-machine interface (BMI). Various neural probes were developed and used to record neuronal action potentials and other brain activities and stimulate the brain neurons. Especially, Si neural probe is one of the essential tools. As the Si neural probe is fabricated by micro and nanotechnologies used for IC and MEMS fabrication, it is possible to realize high-density and multifunctional recording. Our group developed an intelligent Si neural probe system with multifunctional properties. The crucial part of this system is the Si neural probe with high-density recording sites and various sensors. By mounting electrical and chemical sensors on the Si probe, neural activities can be recorded electrically and chemically. Electronic circuits such as low-noise amplifiers, multiplexers, and analog-to-digital converters are integrated at the other end of the intelligent Si neural probe. The neuronal signals recorded from the brain are amplified while keeping a lower noise level. After that, the recorded neuronal signals from the brain are transmitted to the external recording apparatus by wireless connection. To date, it was reported that in vitro and in vivo high-density neural recording with the double-sided Si neural probes. The Si neural probe with a microfluidic channel was fabricated and successfully demonstrated fluid delivery into the brain with a microfluidic channel. Also, the Si opto-neural probe was fabricated with multiple optical waveguides and embedded optical fiber for the optical stimulation of neurons. This presentation will discuss a multifunctional neural probe using semiconductor technologies and a bone marrow implant neural probe that enables recording and manipulating neural activity within the bone marrow. | | 2022年7月2日 15:36～16:00 ラグナガーデンホテル 羽衣：西 第10会場
3S10a-05
中枢自律神経制御ネットワークから骨髄への神経情報伝達
Neural signaling from central autonomic control network to bone marrow
*檜山 武史(1)
1. 岡山大学
*Takeshi Y Hiyama(1)
1. Okayama University
Keyword: Autonomic Nervous System, bone marrow, Sensory nerves, Circumventricular organs
The central autonomic control network involves a group of interconnected areas of the telencephalon, diencephalon, and brainstem that drive the sympathetic outputs via preganglionic neurons in the brainstem and spinal cord. Among these areas, the paraventricular nucleus (PVN) of the hypothalamus has been described as the "autonomic master controller". Many neurons in the parvocellular subnucleus (or the mediocellular region) of PVN project directly and indirectly to the sympathetic pre-ganglionic neurons in the intermediolateralis of the spinal cord. Recent accumulating evidence suggests that bone marrow functions were tightly regulated by the peripheral nervous system. This regulation may be an important mechanism underlying neuro-immune interactions, including the effects of stress on illness. Neural signals also influence the progression of hematological malignancies such as acute and chronic leukemias, and myelomas. The cells produced in the bone marrow egress to the systemic circulation via permeable vasculature sinusoids within the medullary cavity and a part of them return under the control of circadian clock. The PVN receives neural inputs from the sensory circumventricular organs, which lack normal blood-brain barrier and contain the cells expressing the receptors of proinflammatory cytokines. This suggests that these nuclei serve some mechanisms to monitor the state of blood cells in the systemic circulation for blood-cell homeostasis. In this talk, I would like to review the neural pathways from central autonomic network to bone marrow and discuss future challenges to observe and modulate the neural activities in the medullary cavity. | | | |
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