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Mesenchymal stromal cells enhance the engraftment of hematopoietic stem cells in an autologous mouse transplantation model.

Fernández-García M, Yañez RM, Sánchez-Domínguez R, Hernando-Rodriguez M, Peces-Barba M, Herrera G, O'Connor JE, Segovia JC, Bueren JA, Lamana ML - Stem Cell Res Ther (2015)

Bottom Line: This effect was Ad-MSC dose-dependent and associated with an increased homing of transplanted HSCs in recipients' bone marrow.In vivo and in vitro experiments also indicate that the Ad-MSC effects observed in this autologous transplant model are not due to paracrine effects but rather are related to Ad-MSC and HSC interactions, allowing us to propose that Ad-MSCs may act as HSC carriers, facilitating the migration and homing of the HSCs to recipient bone marrow niches.Our results demonstrate that Ad-MSCs facilitate the engraftment of purified HSCs in an autologous mouse transplantation model, opening new perspectives in the application of Ad-MSCs in autologous transplants, including HSC gene therapy.

View Article: PubMed Central - PubMed

Affiliation: Hematopoietic Innovative Therapies Division. Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas (CIEMAT) and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBER-ER), Madrid, Spain. maria.fernandez@ciemat.es.

ABSTRACT

Introduction: Studies have proposed that mesenchymal stem cells (MSCs) improve the hematopoietic engraftment in allogeneic or xenogeneic transplants and this is probably due to the MSCs' immunosuppressive properties. Our study aimed to discern, for the first time, whether MSC infusion could facilitate the engraftment of hematopoietic stem cells (HSCs) in autologous transplantations models, where no immune rejection of donor HSCs is expected.

Methods: Recipient mice (CD45.2) mice, conditioned with moderate doses of radiation (5-7 Gy), were transplanted with low numbers of HSCs (CD45.1/CD45.2) either as a sole population or co-infused with increasing numbers of adipose-derived-MSCs (Ad-MSCs). The influence of Ad-MSC infusion on the short-term and long-term engraftment of donor HSCs was investigated. Additionally, homing assays and studies related with the administration route and with the Ad-MSC/HSC interaction were conducted.

Results: Our data show that the co-infusion of Ad-MSCs with low numbers of purified HSCs significantly improves the short-term and long-term hematopoietic reconstitution of recipients conditioned with moderate irradiation doses. This effect was Ad-MSC dose-dependent and associated with an increased homing of transplanted HSCs in recipients' bone marrow. In vivo and in vitro experiments also indicate that the Ad-MSC effects observed in this autologous transplant model are not due to paracrine effects but rather are related to Ad-MSC and HSC interactions, allowing us to propose that Ad-MSCs may act as HSC carriers, facilitating the migration and homing of the HSCs to recipient bone marrow niches.

Conclusion: Our results demonstrate that Ad-MSCs facilitate the engraftment of purified HSCs in an autologous mouse transplantation model, opening new perspectives in the application of Ad-MSCs in autologous transplants, including HSC gene therapy.

No MeSH data available.


Influence of Ad-MSC administration route on the engraftment of purified HSCs. Donor cell engraftment (fold increase) in the peripheral blood of recipient mice intravenously infused with 1500 LSK cells (white bars), with intravenous co-infusion of 106 Ad-MSCs (gray bars), or with intraperitoneal injection of 106 (striped bars) or 2×106 (dark gray bars) Ad-MSCs. Bars represent standard error of the mean. ***P ≤ 0.001. Ad-MSC adipose tissue-derived mesenchymal stem cell, HSC hematopoietic stem cell, IP intraperitoneal injection, IV intravenous infusion, LSK lineage− Sca-1+ cKit+, ns non-significant difference
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Fig7: Influence of Ad-MSC administration route on the engraftment of purified HSCs. Donor cell engraftment (fold increase) in the peripheral blood of recipient mice intravenously infused with 1500 LSK cells (white bars), with intravenous co-infusion of 106 Ad-MSCs (gray bars), or with intraperitoneal injection of 106 (striped bars) or 2×106 (dark gray bars) Ad-MSCs. Bars represent standard error of the mean. ***P ≤ 0.001. Ad-MSC adipose tissue-derived mesenchymal stem cell, HSC hematopoietic stem cell, IP intraperitoneal injection, IV intravenous infusion, LSK lineage− Sca-1+ cKit+, ns non-significant difference

Mentions: In subsequent experiments represented in Fig. 7, the beneficial engraftment effect of Ad-MSCs was investigated in recipients in which Ad-MSCs (106 cells) were IV co-infused with the LSK cells, with respect to recipients in which the Ad-MSCs were infused via intraperitoneal (IP) injection simultaneously to the IV injection of LSK cells. In previous studies, we demonstrated that an anti-GVHD effect of IV-injected Ad-MSCs is reproduced by IP-administered Ad-MSCs if the cell dose was twofold increased [26]. In our current experiments, doses of 106 or 2×106 Ad-MSCs were, therefore, considered.Fig. 7


Mesenchymal stromal cells enhance the engraftment of hematopoietic stem cells in an autologous mouse transplantation model.

Fernández-García M, Yañez RM, Sánchez-Domínguez R, Hernando-Rodriguez M, Peces-Barba M, Herrera G, O'Connor JE, Segovia JC, Bueren JA, Lamana ML - Stem Cell Res Ther (2015)

Influence of Ad-MSC administration route on the engraftment of purified HSCs. Donor cell engraftment (fold increase) in the peripheral blood of recipient mice intravenously infused with 1500 LSK cells (white bars), with intravenous co-infusion of 106 Ad-MSCs (gray bars), or with intraperitoneal injection of 106 (striped bars) or 2×106 (dark gray bars) Ad-MSCs. Bars represent standard error of the mean. ***P ≤ 0.001. Ad-MSC adipose tissue-derived mesenchymal stem cell, HSC hematopoietic stem cell, IP intraperitoneal injection, IV intravenous infusion, LSK lineage− Sca-1+ cKit+, ns non-significant difference
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4562358&req=5

Fig7: Influence of Ad-MSC administration route on the engraftment of purified HSCs. Donor cell engraftment (fold increase) in the peripheral blood of recipient mice intravenously infused with 1500 LSK cells (white bars), with intravenous co-infusion of 106 Ad-MSCs (gray bars), or with intraperitoneal injection of 106 (striped bars) or 2×106 (dark gray bars) Ad-MSCs. Bars represent standard error of the mean. ***P ≤ 0.001. Ad-MSC adipose tissue-derived mesenchymal stem cell, HSC hematopoietic stem cell, IP intraperitoneal injection, IV intravenous infusion, LSK lineage− Sca-1+ cKit+, ns non-significant difference
Mentions: In subsequent experiments represented in Fig. 7, the beneficial engraftment effect of Ad-MSCs was investigated in recipients in which Ad-MSCs (106 cells) were IV co-infused with the LSK cells, with respect to recipients in which the Ad-MSCs were infused via intraperitoneal (IP) injection simultaneously to the IV injection of LSK cells. In previous studies, we demonstrated that an anti-GVHD effect of IV-injected Ad-MSCs is reproduced by IP-administered Ad-MSCs if the cell dose was twofold increased [26]. In our current experiments, doses of 106 or 2×106 Ad-MSCs were, therefore, considered.Fig. 7

Bottom Line: This effect was Ad-MSC dose-dependent and associated with an increased homing of transplanted HSCs in recipients' bone marrow.In vivo and in vitro experiments also indicate that the Ad-MSC effects observed in this autologous transplant model are not due to paracrine effects but rather are related to Ad-MSC and HSC interactions, allowing us to propose that Ad-MSCs may act as HSC carriers, facilitating the migration and homing of the HSCs to recipient bone marrow niches.Our results demonstrate that Ad-MSCs facilitate the engraftment of purified HSCs in an autologous mouse transplantation model, opening new perspectives in the application of Ad-MSCs in autologous transplants, including HSC gene therapy.

View Article: PubMed Central - PubMed

Affiliation: Hematopoietic Innovative Therapies Division. Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas (CIEMAT) and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBER-ER), Madrid, Spain. maria.fernandez@ciemat.es.

ABSTRACT

Introduction: Studies have proposed that mesenchymal stem cells (MSCs) improve the hematopoietic engraftment in allogeneic or xenogeneic transplants and this is probably due to the MSCs' immunosuppressive properties. Our study aimed to discern, for the first time, whether MSC infusion could facilitate the engraftment of hematopoietic stem cells (HSCs) in autologous transplantations models, where no immune rejection of donor HSCs is expected.

Methods: Recipient mice (CD45.2) mice, conditioned with moderate doses of radiation (5-7 Gy), were transplanted with low numbers of HSCs (CD45.1/CD45.2) either as a sole population or co-infused with increasing numbers of adipose-derived-MSCs (Ad-MSCs). The influence of Ad-MSC infusion on the short-term and long-term engraftment of donor HSCs was investigated. Additionally, homing assays and studies related with the administration route and with the Ad-MSC/HSC interaction were conducted.

Results: Our data show that the co-infusion of Ad-MSCs with low numbers of purified HSCs significantly improves the short-term and long-term hematopoietic reconstitution of recipients conditioned with moderate irradiation doses. This effect was Ad-MSC dose-dependent and associated with an increased homing of transplanted HSCs in recipients' bone marrow. In vivo and in vitro experiments also indicate that the Ad-MSC effects observed in this autologous transplant model are not due to paracrine effects but rather are related to Ad-MSC and HSC interactions, allowing us to propose that Ad-MSCs may act as HSC carriers, facilitating the migration and homing of the HSCs to recipient bone marrow niches.

Conclusion: Our results demonstrate that Ad-MSCs facilitate the engraftment of purified HSCs in an autologous mouse transplantation model, opening new perspectives in the application of Ad-MSCs in autologous transplants, including HSC gene therapy.

No MeSH data available.