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Original author: Anastasia N.
Tikhonova & Iannis Aifantis stimulation paprika at a certain composition, pain nerve cells can be hematopoietic stem cells can be mobilized.
This discovery is expected to improve stem cell transplantation.
The most important feature of blood stem cells is their ability to regenerate the blood and immune system of the whole body.
This process is called hematopoiesis, and these cells are known as hematopoietic stem cells (HSC).
In the developing embryo, hematopoietic stem cells travel in different anatomical parts downstream of the blood circulation.
After birth, these cells exist in a special niche in the bone marrow to support their resting state and self-renewal [1].
During life, hematopoietic stem cells are released from the bone marrow according to the circadian rhythm under the control of the autonomic nerve [2] to replenish blood cells.
Pain nerves are also related to bone marrow, but can these neurons also mobilize hematopoietic stem cells? Gao et al.
[3] published an article in "Nature" to answer this question and pointed out an incredible effect of red pepper.
This work has potential clinical value and biological significance.
For blood cancer patients, such as aggressive leukemia, lymphoma and multiple myeloma, a core part of the treatment after receiving high-dose chemotherapy is autologous stem cell transplantation (ASCT) [4]-Replace the damaged hematopoietic stem cells with healthy hematopoietic stem cells stem cell.
To avoid possible complications, ASCT uses autologous stem cells, which are collected from the blood before chemotherapy and then reinjected through a vein after chemotherapy to regenerate damaged bone marrow.
This process requires a way to encourage healthy hematopoietic stem cells to leave their bone marrow niche and enter the blood, where they can be collected.
Since the 1990s, a secretory factor called granulocyte colony stimulating factor (G-CSF) has been the most commonly used molecular stimulant.
Another stimulant is plexafor approved in 2003, which is a small molecule that prevents hematopoietic stem cells from sticking to bone marrow scaffolds [4].
Since then, people have made progress in different routes of administration and the combination of G-CSF and praxafor.
However, in a small group of people, hematopoietic stem cells are still not fully mobilized.
These people have clinical risk factors including age, genetics, and cancer type (up to 25% of lymphoma patients show poor mobilization), and repeated rounds of chemotherapy [5].
Therefore, it is urgent to understand the molecular mechanism of hematopoietic stem cell mobilization [4].
Source: Pixabay.
Here is an introduction to the research by Gao et al.
They first performed immunofluorescence imaging tests on the bone marrow nerve fibers of mice and found that most of them were nociceptive nerves.
These nociceptors are sensory neurons that cause pain to prevent organisms from danger when they are injured.
Nociceptors exist in any part of the body that can feel harmful stimuli [6].
These neurons in barrier tissues such as skin and intestine have been well studied.
The biological role of nociceptors in non-barrier tissues (such as bone marrow), except for pain, is still rarely studied.
In order to study the possible role of nociceptors in maintaining blood cell production, Gao et al.
used pharmacological and genetic methods to remove these neurons.
This has no effect on the maintenance of hematopoietic stem cells in the bone marrow, but it can significantly reduce the mobilization of hematopoietic stem cells induced by G-CSF into the blood, which indicates that such neurons can affect the adhesion or migration of hematopoietic stem cells.
Calcitonin gene-related peptide (CGRP) is a major neurotransmitter molecule secreted by nociceptor neurons [6].
Gao et al.
found that the use of CGRP can greatly improve the mobilization of hematopoietic stem cells after G-CSF, praxafor or a combination of the two treatments.
They also found that CGRP directly affects hematopoietic stem cells (rather than indirectly through the bone marrow), and induces a combination of calcitonin receptor-like receptor (CALCRL) and receptor activity modifying protein 1 (RAMP1) on the surface of hematopoietic stem cells.
The formation of polyacceptors (Figure 1).
Genetically engineered mice to lack any of them in the bone marrow hematopoietic stem cells will cause problems in HSC mobilization.
Figure 1 | Painful nerve cells regulate hematopoietic stem cell mobilization.
Gao and colleagues [3] reported that most of the nerves in the bone marrow are neurons called nociceptors.
They found that stimulating these nerves through a protein called granulocyte colony stimulating factor (G-CSF) or a component called capsaicin in red pepper (it is not known whether it is a direct or indirect stimulation) will cause the cells to release neurotransmitter molecules.
Calcinin gene-related peptide (CGRP).
In turn, CGRP directly binds to blood stem cells called hematopoietic stem cells (HSC) through a receptor dimer composed of CALCRL and RAMP1 proteins.
This stimulates HSC to move from the bone marrow to the blood vessels.
Clinically, consecutive rounds of chemotherapy often lead to a decrease in the mobilization of hematopoietic stem cells.
Gao et al.
reproduced this phenomenon by treating mice with five cycles of chemotherapy drug cisplatin.
It is worth noting that the use of CGRP can restore the mobilization of hematopoietic stem cells in these mice.
This discovery may be of great significance, or can greatly improve the hematopoietic stem cell collection program for individuals with "weak mobilization ability.
"
Certain types of spicy foods can trigger the activation of nociceptors.
Gao et al.
further thought about whether eating spicy foods can promote the mobilization of hematopoietic stem cells.
In order to test this idea, the author fed the mice a food rich in capsaicin (an active component of red pepper).
This spicy food increases the level of CGRP in the extracellular fluid of bone marrow and increases the mobilization of hematopoietic stem cells induced by CGRP.
When nociceptors were blocked by pharmacological methods, this effect also disappeared, indicating that these neurons mediate the effects of a capsaicin-rich diet.
This paper adds useful information to our understanding of the relationship between the nervous system, bone marrow, and blood cell development.
Early studies using photomicrographs of bone marrow neurons showed that they were innervated by nerve fibers [7].
In the past decade, denervation models of surgery, pharmacology, and genetics have determined the role of the nervous system in regulating the hematopoietic stem cell niche [8].
However, these studies mainly focused on sympathetic nerve fibers (nerve fibers involved in involuntary body movements), indicating that they help maintain the functional integrity of the niche [9].
In this article, Gao et al.
found that the adhesion of hematopoietic stem cells to the bone marrow niche and their ability to mobilize in peripheral blood are controlled by the nociceptive neurons that directly act on hematopoietic stem cells by secreting the neurotransmitter CGRP.
Unexpectedly, the authors did not detect changes in the expression levels of CXCR4, CD44, and VLA4 molecules on the cell surface induced by neurons.
It is known that these molecules are expressed on hematopoietic stem cells and are related to their transport.
Therefore, future research needs to describe the precise mechanism that mediates the mobilization of hematopoietic stem cells after CALCRL-RAMP1 stimulation.
Whether G-CSF directly or indirectly affects nociceptors through other types of cells in the bone marrow is also unclear.
These questions can be answered by targeting cell-type-specific genes in animals.
In addition, research results that are potentially relevant to humans need to be verified in clinical trials, because human biology is often difficult to map perfectly in mice.
Finally, we should also consider the stress response in the bone marrow and its effects on neurons: for example, leukemia induces nerve damage in the bone marrow [10].
Therefore, it is valuable to study the effects of blood cancer and aging on bone marrow nociceptors.
. Despite these problems, we have begun to understand the neuromodulation of blood cell production at the molecular level.
References: 1.
Crane, GM, Jeffery, E.
& Morrison, SJ Nature Rev.
Immunol.
17, 573–590 (2017) 2.
Méndez-Ferrer, S.
, Lucas, D.
, Battista, M.
& Frenette, PS Nature 452, 442–447 (2008) 3.
Gao, X.
et al.
Nature 589, 591–596 (2021).
4.
To, LB, Levesque, J.
-P.
& Herbert, KE Blood 118, 4530–4540 (2011).
5.
Donmez, A.
, Yilmaz, F.
, Gokmen, N.
& Tombuloglu, M.
Transfus.
Apher.
Sci.
49, 485–488 (2013).
6.
Dubin, AE & Patapoutian, AJ Clin.
Invest.
120, 3760–3772 (2010).
7.
Calvo, W.
Am.
J.
Anat.
123, 315–328 (1968).
8.
Agarwala, S.
& Tamplin, OJ Trends Cell .
Biol.
28, 987–998 (2018).
9.
Picoli, CC et al.
Stem Cells Transl.
Med.
https://doi.
org/10.
1002/sctm.
20-0284 (2020).
10.
Hanoun, M .
et al.
Cell Stem Cell 15, 365–375 (2014).
The original article was published under the title Pain-sensing neurons mobilize blood stem cells from bone marrow in the News and Views section of Nature on December 23, 2020 © naturedoi: 10.
1038/d41586-020-03577-7 Natural scientific research paper editing service "Nature"'s high-quality, high-standard manuscript editing service authorservices.
springernature.
cn Language editing.
Native English editors correct language errors in manuscripts, adjust sentence expressions, and improve writing fluency; provide quality assurance and Edit the certificate. Scientific editors Editors with a research background in a specific field conduct a comprehensive review of the manuscript, including: throughout the full text of the review, novelty and impact assessment, strategic reports, language editing, and suggestions for journal submissions.
Other services ★ Academic translation ☆ Manuscript format layout ★ Graphic services [Group discount] Scientific research groups (institutions, laboratories, associations, etc.
) are welcome to purchase natural scientific research paper editing services for group members, and enjoy group discounts and professional after-sales service support.
Contact email: naturecn@nature.
com▲ Scan the QR code to enter the official website of Springer Nature Author Service to view service details and quotations.
Natureportfolio Copyright Statement: This article is translated by Springer Nature Shanghai Office.
The content in Chinese is for reference only, and the original English version shall prevail for all content.
Tikhonova & Iannis Aifantis stimulation paprika at a certain composition, pain nerve cells can be hematopoietic stem cells can be mobilized.
This discovery is expected to improve stem cell transplantation.
The most important feature of blood stem cells is their ability to regenerate the blood and immune system of the whole body.
This process is called hematopoiesis, and these cells are known as hematopoietic stem cells (HSC).
In the developing embryo, hematopoietic stem cells travel in different anatomical parts downstream of the blood circulation.
After birth, these cells exist in a special niche in the bone marrow to support their resting state and self-renewal [1].
During life, hematopoietic stem cells are released from the bone marrow according to the circadian rhythm under the control of the autonomic nerve [2] to replenish blood cells.
Pain nerves are also related to bone marrow, but can these neurons also mobilize hematopoietic stem cells? Gao et al.
[3] published an article in "Nature" to answer this question and pointed out an incredible effect of red pepper.
This work has potential clinical value and biological significance.
For blood cancer patients, such as aggressive leukemia, lymphoma and multiple myeloma, a core part of the treatment after receiving high-dose chemotherapy is autologous stem cell transplantation (ASCT) [4]-Replace the damaged hematopoietic stem cells with healthy hematopoietic stem cells stem cell.
To avoid possible complications, ASCT uses autologous stem cells, which are collected from the blood before chemotherapy and then reinjected through a vein after chemotherapy to regenerate damaged bone marrow.
This process requires a way to encourage healthy hematopoietic stem cells to leave their bone marrow niche and enter the blood, where they can be collected.
Since the 1990s, a secretory factor called granulocyte colony stimulating factor (G-CSF) has been the most commonly used molecular stimulant.
Another stimulant is plexafor approved in 2003, which is a small molecule that prevents hematopoietic stem cells from sticking to bone marrow scaffolds [4].
Since then, people have made progress in different routes of administration and the combination of G-CSF and praxafor.
However, in a small group of people, hematopoietic stem cells are still not fully mobilized.
These people have clinical risk factors including age, genetics, and cancer type (up to 25% of lymphoma patients show poor mobilization), and repeated rounds of chemotherapy [5].
Therefore, it is urgent to understand the molecular mechanism of hematopoietic stem cell mobilization [4].
Source: Pixabay.
Here is an introduction to the research by Gao et al.
They first performed immunofluorescence imaging tests on the bone marrow nerve fibers of mice and found that most of them were nociceptive nerves.
These nociceptors are sensory neurons that cause pain to prevent organisms from danger when they are injured.
Nociceptors exist in any part of the body that can feel harmful stimuli [6].
These neurons in barrier tissues such as skin and intestine have been well studied.
The biological role of nociceptors in non-barrier tissues (such as bone marrow), except for pain, is still rarely studied.
In order to study the possible role of nociceptors in maintaining blood cell production, Gao et al.
used pharmacological and genetic methods to remove these neurons.
This has no effect on the maintenance of hematopoietic stem cells in the bone marrow, but it can significantly reduce the mobilization of hematopoietic stem cells induced by G-CSF into the blood, which indicates that such neurons can affect the adhesion or migration of hematopoietic stem cells.
Calcitonin gene-related peptide (CGRP) is a major neurotransmitter molecule secreted by nociceptor neurons [6].
Gao et al.
found that the use of CGRP can greatly improve the mobilization of hematopoietic stem cells after G-CSF, praxafor or a combination of the two treatments.
They also found that CGRP directly affects hematopoietic stem cells (rather than indirectly through the bone marrow), and induces a combination of calcitonin receptor-like receptor (CALCRL) and receptor activity modifying protein 1 (RAMP1) on the surface of hematopoietic stem cells.
The formation of polyacceptors (Figure 1).
Genetically engineered mice to lack any of them in the bone marrow hematopoietic stem cells will cause problems in HSC mobilization.
Figure 1 | Painful nerve cells regulate hematopoietic stem cell mobilization.
Gao and colleagues [3] reported that most of the nerves in the bone marrow are neurons called nociceptors.
They found that stimulating these nerves through a protein called granulocyte colony stimulating factor (G-CSF) or a component called capsaicin in red pepper (it is not known whether it is a direct or indirect stimulation) will cause the cells to release neurotransmitter molecules.
Calcinin gene-related peptide (CGRP).
In turn, CGRP directly binds to blood stem cells called hematopoietic stem cells (HSC) through a receptor dimer composed of CALCRL and RAMP1 proteins.
This stimulates HSC to move from the bone marrow to the blood vessels.
Clinically, consecutive rounds of chemotherapy often lead to a decrease in the mobilization of hematopoietic stem cells.
Gao et al.
reproduced this phenomenon by treating mice with five cycles of chemotherapy drug cisplatin.
It is worth noting that the use of CGRP can restore the mobilization of hematopoietic stem cells in these mice.
This discovery may be of great significance, or can greatly improve the hematopoietic stem cell collection program for individuals with "weak mobilization ability.
"
Certain types of spicy foods can trigger the activation of nociceptors.
Gao et al.
further thought about whether eating spicy foods can promote the mobilization of hematopoietic stem cells.
In order to test this idea, the author fed the mice a food rich in capsaicin (an active component of red pepper).
This spicy food increases the level of CGRP in the extracellular fluid of bone marrow and increases the mobilization of hematopoietic stem cells induced by CGRP.
When nociceptors were blocked by pharmacological methods, this effect also disappeared, indicating that these neurons mediate the effects of a capsaicin-rich diet.
This paper adds useful information to our understanding of the relationship between the nervous system, bone marrow, and blood cell development.
Early studies using photomicrographs of bone marrow neurons showed that they were innervated by nerve fibers [7].
In the past decade, denervation models of surgery, pharmacology, and genetics have determined the role of the nervous system in regulating the hematopoietic stem cell niche [8].
However, these studies mainly focused on sympathetic nerve fibers (nerve fibers involved in involuntary body movements), indicating that they help maintain the functional integrity of the niche [9].
In this article, Gao et al.
found that the adhesion of hematopoietic stem cells to the bone marrow niche and their ability to mobilize in peripheral blood are controlled by the nociceptive neurons that directly act on hematopoietic stem cells by secreting the neurotransmitter CGRP.
Unexpectedly, the authors did not detect changes in the expression levels of CXCR4, CD44, and VLA4 molecules on the cell surface induced by neurons.
It is known that these molecules are expressed on hematopoietic stem cells and are related to their transport.
Therefore, future research needs to describe the precise mechanism that mediates the mobilization of hematopoietic stem cells after CALCRL-RAMP1 stimulation.
Whether G-CSF directly or indirectly affects nociceptors through other types of cells in the bone marrow is also unclear.
These questions can be answered by targeting cell-type-specific genes in animals.
In addition, research results that are potentially relevant to humans need to be verified in clinical trials, because human biology is often difficult to map perfectly in mice.
Finally, we should also consider the stress response in the bone marrow and its effects on neurons: for example, leukemia induces nerve damage in the bone marrow [10].
Therefore, it is valuable to study the effects of blood cancer and aging on bone marrow nociceptors.
. Despite these problems, we have begun to understand the neuromodulation of blood cell production at the molecular level.
References: 1.
Crane, GM, Jeffery, E.
& Morrison, SJ Nature Rev.
Immunol.
17, 573–590 (2017) 2.
Méndez-Ferrer, S.
, Lucas, D.
, Battista, M.
& Frenette, PS Nature 452, 442–447 (2008) 3.
Gao, X.
et al.
Nature 589, 591–596 (2021).
4.
To, LB, Levesque, J.
-P.
& Herbert, KE Blood 118, 4530–4540 (2011).
5.
Donmez, A.
, Yilmaz, F.
, Gokmen, N.
& Tombuloglu, M.
Transfus.
Apher.
Sci.
49, 485–488 (2013).
6.
Dubin, AE & Patapoutian, AJ Clin.
Invest.
120, 3760–3772 (2010).
7.
Calvo, W.
Am.
J.
Anat.
123, 315–328 (1968).
8.
Agarwala, S.
& Tamplin, OJ Trends Cell .
Biol.
28, 987–998 (2018).
9.
Picoli, CC et al.
Stem Cells Transl.
Med.
https://doi.
org/10.
1002/sctm.
20-0284 (2020).
10.
Hanoun, M .
et al.
Cell Stem Cell 15, 365–375 (2014).
The original article was published under the title Pain-sensing neurons mobilize blood stem cells from bone marrow in the News and Views section of Nature on December 23, 2020 © naturedoi: 10.
1038/d41586-020-03577-7 Natural scientific research paper editing service "Nature"'s high-quality, high-standard manuscript editing service authorservices.
springernature.
cn Language editing.
Native English editors correct language errors in manuscripts, adjust sentence expressions, and improve writing fluency; provide quality assurance and Edit the certificate. Scientific editors Editors with a research background in a specific field conduct a comprehensive review of the manuscript, including: throughout the full text of the review, novelty and impact assessment, strategic reports, language editing, and suggestions for journal submissions.
Other services ★ Academic translation ☆ Manuscript format layout ★ Graphic services [Group discount] Scientific research groups (institutions, laboratories, associations, etc.
) are welcome to purchase natural scientific research paper editing services for group members, and enjoy group discounts and professional after-sales service support.
Contact email: naturecn@nature.
com▲ Scan the QR code to enter the official website of Springer Nature Author Service to view service details and quotations.
Natureportfolio Copyright Statement: This article is translated by Springer Nature Shanghai Office.
The content in Chinese is for reference only, and the original English version shall prevail for all content.
