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Dopamine-mediated Induction of Mesenchymal Progenitor Cell Mobilization for Therapeutic Use

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Review of “Dopamine mobilizes mesenchymal progenitor cells through D2-class receptors and their PI3KAKT pathway” from Stem Cells by Stuart P. Atkinson

The burgeoning field of mesenchymal progenitor cells (MPCs) takes cues from and in some respects is similar to the field of hematopoietic stem cells (HSCs), where the sympathetic nervous system regulates HSC passage from the bone marrow (BM) to the peripheral blood [1]. MPC mobilization and the mode of mobilization to the peripheral blood are relatively unstudied, but MPCs can migrate to injured tissues from their niche [2]. Catecholamines (epinephrine [adrenalin], norepinephrine [noradrenaline] and dopamine) aid the mobilization of HSCs [1, 3, 4], but this has not been observed for MPCs. Now, in a study from the laboratory of Javier García-Castro (Instituto de Salud Carlos III, Madrid, Spain), researchers have demonstrated using in vitro and in vivo analyses that dopamine does play an important role in the migration of MPCs [5].

The researchers first improved a protocol to obtain GCSF (granulocyte colony-stimulating factor) stimulated peripheral blood derived‐MPCs (PB‐MPCs), requiring a high initial concentration of mononuclear cells (MNCs) and using fibronectin as a growth substrate. Isolated cells had a spindle‐shaped morphology, lineage‐differentiation properties, a phenotype similar to real mesenchymal progenitor cells population, potent immunomodulatory properties, and could protect mice against graft vs. host disease as well as bone marrow MPCs. Altogether this suggests that these cells fulfilled criteria descriptive of human MPCs.

The group then discovered that both BM- and PB-MPCs expressed the six subtypes of dopamine receptor and, correlating with this, dopamine addition increased basal migration, with a more pronounced effect in PB-MPCs (see Figure). Agonist/antagonist studies permitted the identification of the D2R‐class receptors as being vital to the dopamine response in MPCs. D2R-class activation usually functions through the inhibition of adenylyl cyclase (AC), but the researchers did not see this effect. Instead, by the understanding that D2R‐class activation can be mediated by transactivation of a tyrosine kinase receptor [6], they identified PI3K/Akt signalling as being important; addition of a PI3K inhibitor reduced the dopamine-mediated increase in MPC migration, while dopamine alone mediated an increase in phosphorylated Akt.

Following this discovery, the group injected mice with catecholamines (dopamine and epinephrine), or G‐CSF as a positive control. Catecholamine injection led to a greater number of PB-MPCs compared to G-CSF and, as before, D2R-class antagonists prevented the dopamine mobilization of mMPCs. The authors then assessed in vivo differentiation potential by attaching cells onto a ceramic compound and implanting into immunodeficient mice. After transplantation the group observed human cells in calcified areas, and fibrous and bone marrow‐like tissues, where MPCs either formed adipose tissue or appeared as interstitial cells. Lastly, the authors assessed the effect of catecholamines on a human patient population (patients with parkinsonian syndrome after a cerebral stroke), finding an enhanced induction of PB-MPCs in the peripheral blood, compared to untreated patients.

Over, this study suggests that catecholamines can mobilize MPCs into peripheral blood. This supports the proposed “brain‐bone‐blood triad” in which some signals affect HSCs directly, while other effects occur indirectly on niche‐supporting stromal cells [7]. This not only delineates how the nervous system regulates stem cells and stem cell niches such as that which exists in the bone marrow, but will also allow us to mobilize more MPCs into the blood for collection and use in clinical applications. Before this can occur, we will require a fuller understanding of markers and expansion conditions in order to obtain a pure enough cells at a high enough number to be relevant.

References

  1. Katayama Y, Battista M, Kao WM, et al. Signals from the sympathetic nervous system regulate hematopoietic stem cell egress from bone marrow. Cell 2006;124:407-421.
  2. Karp JM and Leng Teo GS Mesenchymal stem cell homing: the devil is in the details. Cell Stem Cell 2009;4:206-216.
  3. Rennert RC, Sorkin M, Garg RK, et al. Stem cell recruitment after injury: lessons for regenerative medicine. Regen Med 2012;7:833-850.
  4. Chakroborty D, Chowdhury UR, Sarkar C, et al. Dopamine regulates endothelial progenitor cell mobilization from mouse bone marrow in tumor vascularization. J Clin Invest 2008;118:1380-1389.
  5. Mirones I, Rodriguez MA, Cubillo I, et al. Dopamine mobilizes mesenchymal progenitor cells through D2-class receptors and their PI3K/AKT pathway. Stem Cells 2014;
  6. Neve KA, Seamans JK, and Trantham-Davidson H Dopamine receptor signaling. J Recept Signal Transduct Res 2004;24:165-205.
  7. Spiegel A, Kalinkovich A, Shivtiel S, et al. Stem cell regulation via dynamic interactions of the nervous and immune systems with the microenvironment. Cell Stem Cell 2008;3:484-492.