Bone-marrow-derived microglia: myth or reality?

doi:10.1016/j.coph.2008.04.002

Current Opinion in Pharmacology

Volume 8, Issue 4, August 2008, Pages 508-518

https://doi.org/10.1016/j.coph.2008.04.002 Get rights and content

Microglia are the immune cells of the central nervous system (CNS). They patrol the brain environment with their ramifications and they respond quickly in the presence of pathogens and brain damages. Others and we have recently reported the existence of two different types of microglia, the resident and the newly differentiated microglia that are derived from the bone marrow stem cells. Of great interest is the fact that blood-derived microglial cells are associated with amyloid plaques and these cells are able to prevent the formation or eliminate the presence of amyloid deposits in mice that develop the major hallmark of Alzheimer's disease (AD). These cells are also recruited in the brain of other mouse models of brain diseases and acute injuries. They represent, therefore, a fantastic new vehicle for delivering key molecules to improve recovery, repair, and elimination of toxic proteins. However, recent studies have challenged this concept and raised concerns regarding the physiological relevance of bone-marrow-derived microglia. This review discusses both sides of the story and why the models used to follow the phenotypic fate of these cells are so crucial to reach the proper conclusion. Blood-derived progenitors have the ability to populate the CNS, especially during injuries and chronic diseases. However they do not do it in an efficient manner. Such a lack of proper recruitment may explain the delay in recovery and repair after acute damages and accumulation of toxic proteins in chronic brain diseases.

Introduction

Microglia are the immune cells of the central nervous system (CNS), which are related to macrophages. They represent around 5–20% of the adult brain cell population depending on the specie, and can constitute 20% of the glial cell population. Microglia are distributed throughout the brain and the spinal cord, though they are more abundant in the gray than in the white matter. Importantly, these ramified cells occupy a large volume of the brain parenchyma while forming a dense network that is believed to contribute to the brain homeostasis. Microglia are key players in the cerebral innate immune response. Their role is to actively scan the environment with their highly mobile arms [1] to phagocytose debris and to present antigens to lymphocytes. However, they are not recognized as being very competent antigen-presenting cells (APCs). Microglia have the ability to migrate in the brain parenchyma. Actually, microglia are reported as either in resting (also called quiescent) or activated state. The characterization of these cells is incomplete and their functions are associated with their various morphologies, ranging from amoeboid to ramified ones. During adulthood, it is believed that the proliferation and maintenance of the microglia pool comes from local selfrenewal and infiltration from blood-derived progenitors (Figure 1).

Section snippets

Ontogeny of microglia

The origin of ramified microglia during development has been the scope of a controversial debate between four different hypotheses. It has been proposed that microglia are derived first, from the invasion of mesodermal pial macrophages originating from the yolk sac precursors; second, from neuroectodermal matrix cells; third, from pericytes; and fourth, from the infiltration of monocytes in early development. Stunning similarities exist between cultured microglia and monocytes. Monocyte-derived

Bone-marrow-derived microglia in acute injuries and more chronic brain diseases

Numerous reports have shown that bone-marrow-derived cells (BMDCs) have the ability to populate the CNS and differentiate into functional parenchymal microglia as well as perivascular microglia [8, 9, 10, 11, 12]. Even though BMDCs can enter the brain parenchyma throughout the CNS in normal mice [11], it seems that they are preferentially attracted to regions afflicted by neurodegeneration or neurological insults [9, 10, 12, 13, 14••, 15]. In the case of cerebral ischemia, round donor-derived

Is this a true physiological event?

The recent papers by Ajami et al. [16^••] and Mildner et al. [17^••] raised serious concerns regarding the ability of circulating progenitors to enter and differentiate into functional microglia. Their work suggests that such a phenomenon is a consequence of the generation of chimeric mice using either BMSC transplantation or irradiation. These claims are extremely important for the understanding of the blood-bone-derived microglia infiltration and for the future development of related therapies

Bone-marrow-derived microglia in brain diseases

Many studies have provided evidence that microglial cells are attracted to amyloid deposits both in human samples and in rodent transgenic models that develop Alzheimer's disease (AD) (for a review, please see [14^••]). The precise role of microglia in AD is still under intensive debate. There are two major proposals. One is that these microglia become activated in the presence of β-amyloid and secrete neurotoxic molecules, and the other is that they have neuroprotective actions by secreting

Where to go from now?

It is clear that a better understanding of the role of inflammation in the development of many neurodegenerative diseases is required before we can safely develop new treatments aimed at preventing neuronal damage, improving repair and eliminating toxic proteins. Although an exaggerated immune response can certainly be detrimental to the CNS, increasing evidence demonstrates that a controlled inflammatory reaction in the brain can be greatly beneficial to the health and proper function of the

References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

•• of outstanding interest

Acknowledgements

The Canadian Institutes in Health Research (CIHR) supports this research. Denis Soulet is current postdoc fellow at the Neuronal Survival Unit, Wallenberg Neurocentrum, Lund University, Sweden. Serge Rivest holds a Canadian Research Chair in Neuroimmunology.

References (52)

A.V. Andjelkovic et al.
Macrophages/microglial cells in human central nervous system during development: an immunohistochemical study
Brain Res
(1998)
W.Y. Chan et al.
The origin and cell lineage of microglia: new concepts
Brain Res Rev
(2007)
A.R. Simard et al.
Bone marrow-derived microglia play a critical role in restricting senile plaque formation in Alzheimer's disease
Neuron
(2006)
R.B. Harris et al.
Recombinant leptin exchanges between parabiosed mice but does not reach equilibrium
Am J Physiol
(1997)
M. Meyer-Luehmann et al.
Rapid appearance and local toxicity of amyloid-beta plaques in a mouse model of Alzheimer's disease
Nature
(2008)
S. Hashioka et al.
Amyloid-beta fibril formation is not necessarily required for microglial activation by the peptides
Neurochem Int
(2005)
J. Wegiel et al.
The role of microglial cells and astrocytes in fibrillar plaque evolution in transgenic APP(SW) mice
Neurobiol Aging
(2001)
S. Walsh et al.
Inflammatory processes and Alzheimer's disease
Expert Rev Neurother
(2004)
T. Kukar et al.
Diverse compounds mimic Alzheimer disease-causing mutations by augmenting Abeta42 production
Nat Med
(2005)
V. Blais et al.
Cyclooxygenase 2 (COX-2) inhibition increases the inflammatory response in the brain during systemic immune stimuli
J Neurochem
(2005)

F.S. Shie et al.

Microglia lacking E prostanoid receptor subtype 2 have enhanced Abeta phagocytosis yet lack Abeta-activated neurotoxicity

Am J Pathol

(2005)

W.J. Streit

Microglia and neuroprotection: implications for Alzheimer's disease

Brain Res Brain Res Rev

(2005)

K. Tahara et al.

Role of toll-like receptor signalling in Abeta uptake and clearance

Brain

(2006)

V.H. Perry et al.

Immunohistochemical localization of macrophages and microglia in the adult and developing mouse brain

Neuroscience

(1985)

E.A. Ling et al.

Immunocytochemical localization of CR3 complement receptors with OX-42 in amoeboid microglia in postnatal rats

Anat Embryol (Berl)

(1990)

W.W. Htain et al.

In vivo expression of inducible nitric oxide synthase in supraventricular amoeboid microglial cells in neonatal BALB/c and athymic mice

Neurosci Lett

(1997)

A. Nimmerjahn et al.

Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo

Science

(2005)

K. Imamoto et al.

Radioautographic investigation of gliogenesis in the corpus callosum of young rats. II. Origin of microglial cells

J Comp Neurol

(1978)

E.A. Ling

Transformation of monocytes into amoeboid microglia in the corpus callosum of postnatal rats, as shown by labelling monocytes by carbon particles

J Anat

(1979)

C. Kaur et al.

Origin and fate of neural macrophages in a stab wound of the brain of the young rat

J Anat

(1987)

S.K. Leong et al.

Amoeboid and ramified microglia: their interrelationship and response to brain injury

Glia

(1992)

M. Massengale et al.

Hematopoietic cells maintain hematopoietic fates upon entering the brain

J Exp Med

(2005)

J. Priller et al.

Targeting gene-modified hematopoietic cells to the central nervous system: use of green fluorescent protein uncovers microglial engraftment

Nat Med

(2001)

J. Priller et al.

Neogenesis of cerebellar Purkinje neurons from gene-marked bone marrow cells in vivo

J Cell Biol

(2001)

A.R. Simard et al.

Bone marrow stem cells have the ability to populate the entire central nervous system into fully differentiated parenchymal microglia

FASEB J

(2004)

L. Vallieres et al.

Bone marrow-derived cells that populate the adult mouse brain preserve their hematopoietic identity

J Neurosci

(2003)

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Bone-marrow-derived microglia: myth or reality?

Introduction

Section snippets

Ontogeny of microglia

Bone-marrow-derived microglia in acute injuries and more chronic brain diseases

Is this a true physiological event?

Bone-marrow-derived microglia in brain diseases

Where to go from now?

References and recommended reading

Acknowledgements

Brain Res

Brain Res Rev

Neuron

Am J Physiol

Nature

Neurochem Int

Neurobiol Aging

Expert Rev Neurother

Nat Med

J Neurochem

Am J Pathol

Brain Res Brain Res Rev

Brain

Neuroscience

Anat Embryol (Berl)

Neurosci Lett

Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo

Science

Radioautographic investigation of gliogenesis in the corpus callosum of young rats. II. Origin of microglial cells

J Comp Neurol

Transformation of monocytes into amoeboid microglia in the corpus callosum of postnatal rats, as shown by labelling monocytes by carbon particles

J Anat

Origin and fate of neural macrophages in a stab wound of the brain of the young rat

J Anat

Amoeboid and ramified microglia: their interrelationship and response to brain injury

Glia

Hematopoietic cells maintain hematopoietic fates upon entering the brain

J Exp Med

Targeting gene-modified hematopoietic cells to the central nervous system: use of green fluorescent protein uncovers microglial engraftment

Nat Med

Neogenesis of cerebellar Purkinje neurons from gene-marked bone marrow cells in vivo

J Cell Biol

Bone marrow stem cells have the ability to populate the entire central nervous system into fully differentiated parenchymal microglia

FASEB J

Bone marrow-derived cells that populate the adult mouse brain preserve their hematopoietic identity

J Neurosci