10.4081/btvb.2022.29
For many years, the brain was considered as a closed system protected by the blood-brain barrier (BBB), where only the hormones produced by the body can mediate the interplay between the brain and the blood. Indeed, hormones, crossing the BBB and binding to specific receptors on the brain cells, regulates neuronal and synaptic plasticity and neurogenesis [...].
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Silvia Stella Barbieri
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Bleeding, Thrombosis and Vascular Biology
neurogenesis
Are platelets more than a model of brain neurons?
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2022-03-24
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Bleed Thromb Vascul Biol
Silvia Stella Barbieri
2022/05/12
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Wang Q, Wei J and Shi Y. Platelet microvesicles promote the recovery of neurological function in mouse model of cerebral infarction by inducing angiogenesis. Biochem Biophys Res Commun 2019;513:997-1004
Are platelets more than a model of brain neurons?
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                                                                                                                       EDITORIAL

Are platelets more than a model of brain neurons?
Ilaria Canobbio,1 Silvia Stella Barbieri2

Department of Biology and Biotechnology, University of Pavia, Italy; 2Unit of Brain-Heart Axis, Cellular and Molecular Mechanisms,
1

Centro Cardiologico Monzino IRCCS, Milan, Italy




    For many years, the brain was considered as a closed                      throughout the human body, whereas platelets play a role
system protected by the blood-brain barrier (BBB), where                      in hemostasis, thrombosis, inflammation, immunity and
only the hormones produced by the body can mediate the                        tissue regeneration.3 However, growing evidence in the
interplay between the brain and the blood. Indeed, hor-                       past decade supports the notion that circulating platelets
mones, crossing the BBB and binding to specific recep-                        and brain neurons are closely intertwined and share com-
tors on the brain cells, regulates neuronal and synaptic                      mon features.
plasticity and neurogenesis. In this context, the crosstalk                       First, neurons and platelets realize a functional net-
between brain and blood cells was thought unlikely under                      work of interconnected cells, and exchange paracrine




                                                                                              ly
physiological conditions. More recently, this picture                         bioactive messengers to fully accomplish their function.




                                                                                       on
changed: several evidence suggest that the platelets, the                     These essential metabolites are contained in specific gran-
smallest blood cells, may facilitate communication be-                        ules both in neurons and in platelets (α-granules and dense
tween the blood and the brain.1                                               granules) and released upon activation.4 Second, some



                                                                                  e
    No doubt, platelets and neurons are different cells:2                     proteins that are present in neurons with specific neuronal
                                                                             us
they have different embryological origin as neurons de-                       function, are also highly expressed in platelets with phys-
rive from the neuroectoderm and platelets from meso-                          iological relevance.5 Striking example of proteins shared
derm; neurons are resident cells with very poor                               between neurons and platelets are the neurotransmitter
                                                                             al

regenerative capacity, while platelets are circulating cells                  serotonin and transporter/enzymes involved in its metab-
                                                          ci

with a reasonable turnover, with a life span of 8-10 days;                    olism,6,7 the neurotrophic factors reelin,8 Brain-Derived
neurons are the fundamental units of the brain and nerv-                      Neurotrophic Factor (BDNF),9 the amyloid precursor pro-
                                                        er



ous system, and are responsible for carrying information                      tein (APP)10 and its metabolites amyloid Aβ peptides.11
                                                       m




                                                                              Since platelets lack a nucleus, these proteins may mainly
                                                                              derive from platelet precursors, the megakaryocytes, or
                                            om




                                                                              be translated from small amount of residual mRNA, or in-
    Correspondence: Ilaria Canobbio, Department of Biology and
                                                                              ternalized from the bloodstream. In the latter case, it
                                                                              should be argued that platelets hike molecules throughout
                                     -c




    Biotechnology, University of Pavia, via Bassi 21, 27100 Pavia,
    Italy.                                                                    the body thus allowing the redistribution of bioactive
                            on




    Tel.: +39.0382987238.                                                     modulators. The reason of the unusual presence of neu-
    E-mail: ilaria.canobbio@unipv.it
                                                                              ronal proteins in platelets is not known, but the practical
                                                                              consequences are evident. It has been shown, in fact, that
                      N




    Key words: Platelets, Neurons, Extracellular vesicles, miRNA,
    Blood-brain connection, Neurogenesis.                                     neurological disorders in which these proteins are dys-
                                                                              functional (mood disorders, autism spectrum disorder, de-
    Contributions: The authors contributed equally.
                                                                              pression, Parkinson and Alzheimer disease) have also a
    Conflict of interest: The authors declare no potential conflict of in-    counterpart in platelet dysfunction.12,13       Epidemio-
    terest.                                                                   logical and genetic studies showed that patients with neu-
                                                                              rodegenerative and neuropsychiatric traits displayed
    Funding: None.
                                                                              enhanced platelet hyper-reactivity, as suggested by the in-
    Received for publication: 24 March 2022.                                  creased aggregability, expression of platelet αIIbβ3 and
    Accepted for publication: 21 April 2022.                                  P-selectin, and percentage of platelet/leukocyte aggre-
                                                                              gates. In addition, a higher MPV (mean platelet volume),
    This work is licensed under a Creative Commons Attribution Non-
    Commercial 4.0 License (CC BY-NC 4.0).                                    platelet distribution width (PDW) and/or platelet-to-larger
                                                                              cell ratio (P-LCR) have been detected in subject with de-
    ©
     Copyright: the Author(s), 2022                                           pression, anxiety disorder, patients affected by Parkinson
    Licensee PAGEPress, Italy                                                 and Alzheimer diseases.12,13
    Bleeding, Thrombosis and Vascular Biology 2022; 1:29
    doi:10.4081/btvb.2022.29                                                      A genetic overlap of platelet parameters with neurode-
                                                                              generative-psychiatric disease has been recently sug-

                                                Bleeding, Thrombosis and Vascular Biology 2022; 1:29
46                                                I. Canobbio and S.S. Barbieri




gested. In a very elegant study, Tirozzi et al. showed an           specific brain areas in relation to pathological and physi-
association between MPV and genes, as ARHGEF3,                      ological conditions.
KALRN and IQGAP2, previously related with depression,                   Despite that, the use of platelet products in different
Alzheimer Disease, schizophrenia and Parkinson Disease;             medical applications (ranging from stroke to neurodegen-
they suggested a potential coagulation, megakaryocyte               erative diseases) is of particular interest in recent years,
development and platelet production pathway as common               however, how platelet-brain cell communication occurs
link between platelet abnormality and neuropathological             remains to be established. Both soluble proteins and ex-
dysfunction.14                                                      tracellular vesicles released by activated platelets may be
     More interestingly, platelets and their released factors       considered good candidates.
may directly participate in the modulation of brain plas-               Heterochronic parabiosis experiments provided evi-
ticity. In recent years, the use of platelet products in dif-       dence of the presence of “anti-aging” or “pro-aging” fac-
ferent      medical      applications,     ranging       from       tors in blood of young and old mice, respectively.
neurodegenerative diseases to stroke, and the beneficial            Katsimpardi et al. showed that a grow factor highly con-
effect of platelet-rich plasma in animal models of neu-             centrated in platelets (GDF11)24 had great neurogenesis
rodegenerative diseases is well consolidated. In a mouse            potential,25 supporting a platelet-centric model in the
model of Parkinson’s diseases, intranasal administration            blood-brain connection.
of human platelet lysates as well as plasma enriched in                 The possible key role of extracellular vesicles platelet-




                                                                                              ly
platelet secretome displayed a neuroprotective effect in            generated (PMP) in this interplay has been proposed based




                                                                                      on
the substantia nigra and striatum.15,16 Similarly, in a mouse       on: the parallelism found between the miRNAs detected in
model of Alzheimer’s disease, chronic intranasal admin-             PMP and those expressed in the brain from Alzheimer dis-
istration of plasma enriched in platelet secretoma reduced          ease patients;26 the identification of specific platelet miR-



                                                                                  e
neuropathologic hallmarks, improved cognitive functions             NAs among those candidate as biomarkers of multiple
and decreased amyloid Aβ peptides deposits and tau hy-
                                                                         us
                                                                    sclerosis;26 the in vivo neurogenic and angiogenic effects
perphosphorylation.17                                               induced by PMP in adult rats after cerebral infarction.27
     It has been proposed that under pathological condi-                Following these considerations, we can assert that:
                                                                  al

tions, platelets can directly recognize the neuronal dam-           yes, platelets are more than a model of neurons! We can
                                                      ci

age,18 accumulate in the brain along the vasculature, and           here emphasize that platelets play a crucial role that is not
by secreting their content, regulate inflammation and               limited to hemostasis and thrombosis but goes far beyond
                                                    er



stimulate neuronal functions and synaptic plasticity.19 The         them.3,13
                                                   m




presence of platelets within the zone rich in neural stem
and progenitor cells has been found and associated with
                                          om




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                                     -c




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