Endocannabinoids as positive or negative factors in hematopoietic cell migration and differentiation

Patinkin, Deborah; Milman, Garry; Breuer, Aviva; Fride, Ester; Mechoulam, Raphael

doi:10.1016/j.ejphar.2008.05.002

Cited by 38 publications

(37 citation statements)

References 18 publications

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“…In this context, it is noteworthy that eCBs can be counted among factors that govern haematopoietic stem cell biology. In bone marrow, CB receptors are highly expressed in haematopoietic stem cells, [51][52][53] and stromal cells release significant amounts of eCBs that modulate differentiation and migration, alone or in synergy with classical growth factors. 51,52 Therefore, it is tempting to speculate that pharmacological alteration of 2-AG tone in specialized niches of bone marrow would affect self-renewal and differentiation of haematopoietic cells, as well as lineage commitment.…”

Section: Discussionmentioning

confidence: 99%

“…In bone marrow, CB receptors are highly expressed in haematopoietic stem cells, [51][52][53] and stromal cells release significant amounts of eCBs that modulate differentiation and migration, alone or in synergy with classical growth factors. 51,52 Therefore, it is tempting to speculate that pharmacological alteration of 2-AG tone in specialized niches of bone marrow would affect self-renewal and differentiation of haematopoietic cells, as well as lineage commitment. 54 In addition, owing to the specific effect of 2-AG on megakaryocyte precursors, it would be helpful to manage bone marrow failure and blood cell loss occurring in several pathological conditions.…”

Section: Discussionmentioning

confidence: 99%

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2-Arachidonoylglycerol enhances platelet formation from human megakaryoblasts

et al. 2014

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Platelets modulate vascular system integrity, and their loss is critical in haematological pathologies and after chemotherapy. Therefore, identification of molecules enhancing platelet production would be useful to counteract thrombocytopenia. We have previously shown that 2-arachidonoylglycerol (2-AG) acts as a true agonist of platelets, as well as it commits erythroid precursors toward the megakaryocytic lineage. Against this background, we sought to further interrogate the role of 2-AG in megakaryocyte/platelet physiology by investigating terminal differentiation, and subsequent thrombopoiesis. To this end, we used MEG-01 cells, a human megakaryoblastic cell line able to produce in vitro platelet-like particles.2-AG increased the number of cells showing ruffled surface and enhanced surface expression of specific megakaryocyte/platelet surface antigens, typical hallmarks of terminal megakaryocytic differentiation and platelet production. Changes in cytoskeleton modeling also occurred in differentiated megakaryocytes and blebbing platelets. 2-AG acted by binding to CB 1 and CB 2 receptors, because specific antagonists reverted its effect. Platelets were split off from megakaryocytes and were functional: they contained the platelet-specific surface markers CD61 and CD49, whose levels increased following stimulation with a natural agonist like collagen. Given the importance of 2-AG for driving megakaryopoiesis and thrombopoiesis, not surprisingly we found that its hydrolytic enzymes were tightly controlled by classical inducers of megakaryocyte differentiation.In conclusion 2-AG, by triggering megakaryocyte maturation and platelet release, may have clinical efficacy to counteract thrombocytopenia-related diseases.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

2-Arachidonoylglycerol enhances platelet formation from human megakaryoblasts

et al. 2014

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“…It seems, however, that the two main endocannabinoids may play different roles in this context: AEA reduces, while 2-AG enhances, bone marrow cell migration, and both enhance the formation of granulocyte, erythrocyte, macrophage, and megakaryocyte colonies, AEA being more potent than 2-AG (666). Endocannabinoids released from stromal cells exert distinct effects on mesoderm-derived hematopoietic and mesenchymal stem cell differentiation and migration determining the formation of several cell types alone or in synergy with classical growth factors (279,666). The effects occur through CB2 activation (666,866).…”

Section: Immune Systemmentioning

confidence: 99%

“…Endocannabinoids released from stromal cells exert distinct effects on mesoderm-derived hematopoietic and mesenchymal stem cell differentiation and migration determining the formation of several cell types alone or in synergy with classical growth factors (279,666). The effects occur through CB2 activation (666,866). Furthermore, 2-AG is able to drive a cell line expressing surface antigens of both erythroid and megakaryocytic phenotypes towards megakaryocytic differentiation (128), thereby stimulating platelet production and release (285).…”

Section: Immune Systemmentioning

confidence: 99%

From Phytocannabinoids to Cannabinoid Receptors and Endocannabinoids: Pleiotropic Physiological and Pathological Roles Through Complex Pharmacology

Ligresti¹,

Petrocellis²,

Marzo³

2016

Physiological Reviews

380

337

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Apart from having been used and misused for at least four millennia for, among others, recreational and medicinal purposes, the cannabis plant and its most peculiar chemical components, the plant cannabinoids (phytocannabinoids), have the merit to have led humanity to discover one of the most intriguing and pleiotropic endogenous signaling systems, the endocannabinoid system (ECS). This review article aims to describe and critically discuss, in the most comprehensive possible manner, the multifaceted aspects of 1) the pharmacology and potential impact on mammalian physiology of all major phytocannabinoids, and not only of the most famous one ⌬ 9 -tetrahydrocannabinol, and 2) the adaptive prohomeostatic physiological, or maladaptive pathological, roles of the ECS in mammalian cells, tissues, and organs. In doing so, we have respected the chronological order of the milestones of the millennial route from medicinal/recreational cannabis to the ECS and beyond, as it is now clear that some of the early steps in this long path, which were originally neglected, are becoming important again. The emerging picture is rather complex, but still supports the belief that more important discoveries on human physiology, and new therapies, might come in the future from new knowledge in this field.

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“…Because eCBs broadly affect cell proliferation, fate, motility, and differentiation (e.g., in sperm, hematopoietic and T cells, and neurons) (10)(11)(12)(13), it is likely that they play a role in the cellular organization of developing pancreatic islets, possibly by affecting the spatial segregation of α and β cells. A contribution of eCBs to cell diversification and positioning in the developing pancreas is supported by the temporal control of their levels in fetal tissues (14) and circulation (15).…”

mentioning

confidence: 99%

Fetal endocannabinoids orchestrate the organization of pancreatic islet microarchitecture

Malenczyk

Keimpema

Piscitelli

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Endocannabinoids are implicated in the control of glucose utilization and energy homeostasis by orchestrating pancreatic hormone release. Moreover, in some cell niches, endocannabinoids regulate cell proliferation, fate determination, and migration. Nevertheless, endocannabinoid contributions to the development of the endocrine pancreas remain unknown. Here, we show that α cells produce the endocannabinoid 2-arachidonoylglycerol (2-AG) in mouse fetuses and human pancreatic islets, which primes the recruitment of β cells by CB 1 cannabinoid receptor (CB 1 R) engagement. Using subtractive pharmacology, we extend these findings to anandamide, a promiscuous endocannabinoid/endovanilloid ligand, which impacts both the determination of islet size by cell proliferation and α/β cell sorting by differential activation of transient receptor potential cation channel subfamily V member 1 (TRPV1) and CB 1 Rs. Accordingly, genetic disruption of TRPV1 channels increases islet size whereas CB 1 R knockout augments cellular heterogeneity and favors insulin over glucagon release. Dietary enrichment in ω-3 fatty acids during pregnancy and lactation in mice, which permanently reduces endocannabinoid levels in the offspring, phenocopies CB 1 R −/− islet microstructure and improves coordinated hormone secretion. Overall, our data mechanistically link endocannabinoids to cell proliferation and sorting during pancreatic islet formation, as well as to life-long programming of hormonal determinants of glucose homeostasis.A nandamide (AEA) and 2-arachydonoylglycerol (2-AG), major endocannabinoids (eCBs), are involved in the regulation of energy homeostasis through coordinated actions in peripheral organs (adipose tissue, liver, and pancreas) and brain (hypothalamus, ventral striatum) (1). eCB signals are particularly significant to coordinate the regulated release of insulin and glucagon from mature pancreatic islets (2-6). Genetic evidence from CB 1 cannabinoid receptor −/− (CB 1 R −/− ) mice supports these findings because CB 1 R −/− mice are lean, resistant to high fat diet-induced obesity and diabetes (4, 7-9). Whether eCBs impact the formation of the endocrine pancreas and predispose it to long-lasting changes in hormone release postnatally remains unknown.Because eCBs broadly affect cell proliferation, fate, motility, and differentiation (e.g., in sperm, hematopoietic and T cells, and neurons) (10-13), it is likely that they play a role in the cellular organization of developing pancreatic islets, possibly by affecting the spatial segregation of α and β cells. A contribution of eCBs to cell diversification and positioning in the developing pancreas is supported by the temporal control of their levels in fetal tissues (14) and circulation (15). Moreover, α and β cells in mature pancreatic islets express the molecular machinery for eCB metabolism together with CB 1 Rs and transient receptor potential cation channels, particularly subfamily V member 1 (TRPV1) (2,16,17). Understanding these developmental processes is also relevant to po...

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Endocannabinoids as positive or negative factors in hematopoietic cell migration and differentiation

Cited by 38 publications

References 18 publications

2-Arachidonoylglycerol enhances platelet formation from human megakaryoblasts

2-Arachidonoylglycerol enhances platelet formation from human megakaryoblasts

From Phytocannabinoids to Cannabinoid Receptors and Endocannabinoids: Pleiotropic Physiological and Pathological Roles Through Complex Pharmacology

Fetal endocannabinoids orchestrate the organization of pancreatic islet microarchitecture

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