Bovine peripheral blood MSCs chemotax towards inflammation and embryo implantation stimuli

Abstract

Mesenchymal stem cells (MSCs) have a great potential in regenerative medicine because of their multipotential and immunoregulatory capacities, while in early pregnancy they could participate in the immunotolerance of the mother towards the embryo. Peripheral blood constitutes an accessible source of MSCs. We successfully isolated peripheral blood MSC (pbMSCs) lines, with or without previous bone marrow mobilization. All pbMSCs lines obtained in both conditions presented classical MSC markers and properties, alkaline phosphatase activity and multipotent capacity to differentiate among adipogenic, osteogenic or chondrogenic lineages, and suppressed the proliferation of T cells. pbMSCs showed migratory capacity without cytokine stimulation while increasing their migration rate in the presence of inflammatory or embryo implantation stimuli. Interestingly, in contrast to MSCs derived from endometrial tissue, three pbMSCs lines also showed increased migration towards the IFN-τ implantation cytokine. Moreover, the secretome produced by an early implantation stage embryonic trophectoderm cell line showed a chemoattractant effect in pbMSCs. Our results suggest that circulating MSCs are present in the peripheral blood under healthy conditions. The fact that both the inflammation and implantation signals induced pbMSCs chemotaxis highlights MSC heterogeneity and suggests that their migratory capacity may differ according to their tissue of origin and would suggest the possible active recruitment of MSCs from bone marrow during pregnancy to repress the immune response to prevent the embryo rejection by the maternal organism.

Embryonic Trophectoderm Secretomics Reveals Chemotactic Migration and Intercellular Communication of Endometrial and Circulating MSCs in Embryonic Implantation

“…Recently, our group characterized for the first time endometrial mesenchymal stem cell lines (eMSC) [ 11 ] as well as peripheral blood MSC (pbMSCs) lines [ 12 ]. While eMSC showed a reduced migratory capacity in response to the implantation cytokine IFN-τ [ 11 ], pbMSC showed chemotactic behavior to both inflammation (TNFα, IL1β), embryo implantation stimuli (IFN-τ) or BBT-secretome, suggesting that the embryo secretome plays a role in ensuring the retention of eMSC and the active recruitment of MSCs from bone marrow during early pregnancy to repress the immune response to prevent the embryo rejection by the maternal organism [ 12 ].…”

“…Therefore, the BBT-9, thanks to its mesenchymal phenotype, could play an immunomodulatory role via EV signaling, aimed at guaranteeing the survival of the embryo. Our group has also reported the immunomodulatory capacity of eMSC and pbMSC by inhibiting the proliferation of human T lymphocytes [ 11 , 12 ].…”

“…Our results would thus suggest that circulating MSCs are present in the peripheral blood under healthy conditions and can be actively recruited to the implantation niche during pregnancy. Retention of eMSC and recruitment of pbMSC would ensure the necessary immunorepression to prevent embryo rejection by the maternal organism [ 12 ].…”

IL1B triggers inflammatory cytokine production in bovine oviduct epithelial cells and induces neutrophil accumulation via CCL2

“…Moreover, CCL2 plays a role in the recruitment of immune regulatory cells to implantation sites within the bovine endometrium 47 . Interestingly, Calle et al 48,49 reported that bovine mesenchymal stem cells from peripheral blood and endometrium migrate toward for inflammatory stimuli and/or implantation cytokine (interferon‐tau) to ensure the immunomodulation necessary in the mother for embryo survival. Therefore, inflammatory conditions in the oviduct are expected to contribute to both physiological conditions for pregnancy, such as embryo development, and pathological conditions, such as infertility, and further detailed examination is required.…”

Conceptus-modulated innate immune function during early pregnancy in ruminants: a review

“…The mesenteric lymph nodes also express ISG15 (Oliveira et al, 2008) and the traffic of immune cells through that could be a source of IFN-τ stimulus. Additionally, there are in vitro evidence that peripheral blood mesenchymal stem cells (pbMSC) increase their migratory capacity in response to IFN-τ treatment, which could be a chemotaxis stimulus to the uterus (Calle et al, 2021). Immune cells have important roles during pregnancy establishment (Berkowitz et al, 1988;Fair, 2015); however, the functions for each ISG up regulated in PBMC and PMN have not been determined.…”