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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.


Ad-MSC dose-dependent effect on HSC engraftment transplanted into congenic recipients conditioned with moderate radiation. a Fold-increase of donor hematopoietic engraftment in peripheral blood of 5 Gy-irradiated recipient mice transplanted with 1500 LSK cells co-infused with increasing numbers of Ad-MSCs. b Evolution of peripheral blood donor engraftment in the peripheral blood of recipient mice co-infused with 1500 LSK plus 6×105 or 106 Ad-MSCs. Data obtained at 4, 8, and 12 weeks post-transplantation are shown. Bars represent standard error of the mean. *P ≤ 0.05. ***P ≤ 0.001. Ad-MSC adipose tissue-derived mesenchymal stem cell, HSC hematopoietic stem cell, HSCT hematopoietic stem cell transplant, LSK lineage− Sca-1+ cKit+, ns non-significant difference
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Fig3: Ad-MSC dose-dependent effect on HSC engraftment transplanted into congenic recipients conditioned with moderate radiation. a Fold-increase of donor hematopoietic engraftment in peripheral blood of 5 Gy-irradiated recipient mice transplanted with 1500 LSK cells co-infused with increasing numbers of Ad-MSCs. b Evolution of peripheral blood donor engraftment in the peripheral blood of recipient mice co-infused with 1500 LSK plus 6×105 or 106 Ad-MSCs. Data obtained at 4, 8, and 12 weeks post-transplantation are shown. Bars represent standard error of the mean. *P ≤ 0.05. ***P ≤ 0.001. Ad-MSC adipose tissue-derived mesenchymal stem cell, HSC hematopoietic stem cell, HSCT hematopoietic stem cell transplant, LSK lineage− Sca-1+ cKit+, ns non-significant difference

Mentions: To investigate whether the engraftment effect of Ad-MSCs was dose-dependent, 1500 LSK cells were co-infused with increasing numbers of Ad-MSCs (from 2×105 Ad-MSCs to 106 Ad-MSCs/mouse) in 5 Gy-irradiated recipients (Fig. 3). Analyses performed 4 weeks after transplant showed that the co-infusion of 2×105 Ad-MSCs did not increase the engraftment of LSK cells, as compared with data obtained when the LSK cells were transplanted as a sole population. In contrast to this data, the co-infusion of 4×105 Ad-MSCs mediated a significant increase in the engraftment of LSK cells, an observation that was even more marked when 6×105 Ad-MSCs/mouse were co-infused. No further increments were observed in the group co-infused with 106 Ad-MSCs (Fig. 3a). When analyses were performed at 8 and 12 weeks after transplant, doses of 6×105 and 106 Ad-MSCs still showed improvements in the engraftment of purified LSK cells (see fold increases of engraftment in Fig. 3a and representative absolute values of engraftment in Fig. 3b). These results thus demonstrate that the hematopoietic engraftment effect of Ad-MSCs is dose-dependent. Additionally, our data indicate that relatively low doses of Ad-MSCs can accelerate the engraftment of transplanted LSK cells but that higher Ad-MSC doses are required to improve LSK cell engraftment in later stages post-transplantation.Fig. 3


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)

Ad-MSC dose-dependent effect on HSC engraftment transplanted into congenic recipients conditioned with moderate radiation. a Fold-increase of donor hematopoietic engraftment in peripheral blood of 5 Gy-irradiated recipient mice transplanted with 1500 LSK cells co-infused with increasing numbers of Ad-MSCs. b Evolution of peripheral blood donor engraftment in the peripheral blood of recipient mice co-infused with 1500 LSK plus 6×105 or 106 Ad-MSCs. Data obtained at 4, 8, and 12 weeks post-transplantation are shown. Bars represent standard error of the mean. *P ≤ 0.05. ***P ≤ 0.001. Ad-MSC adipose tissue-derived mesenchymal stem cell, HSC hematopoietic stem cell, HSCT hematopoietic stem cell transplant, 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

Fig3: Ad-MSC dose-dependent effect on HSC engraftment transplanted into congenic recipients conditioned with moderate radiation. a Fold-increase of donor hematopoietic engraftment in peripheral blood of 5 Gy-irradiated recipient mice transplanted with 1500 LSK cells co-infused with increasing numbers of Ad-MSCs. b Evolution of peripheral blood donor engraftment in the peripheral blood of recipient mice co-infused with 1500 LSK plus 6×105 or 106 Ad-MSCs. Data obtained at 4, 8, and 12 weeks post-transplantation are shown. Bars represent standard error of the mean. *P ≤ 0.05. ***P ≤ 0.001. Ad-MSC adipose tissue-derived mesenchymal stem cell, HSC hematopoietic stem cell, HSCT hematopoietic stem cell transplant, LSK lineage− Sca-1+ cKit+, ns non-significant difference
Mentions: To investigate whether the engraftment effect of Ad-MSCs was dose-dependent, 1500 LSK cells were co-infused with increasing numbers of Ad-MSCs (from 2×105 Ad-MSCs to 106 Ad-MSCs/mouse) in 5 Gy-irradiated recipients (Fig. 3). Analyses performed 4 weeks after transplant showed that the co-infusion of 2×105 Ad-MSCs did not increase the engraftment of LSK cells, as compared with data obtained when the LSK cells were transplanted as a sole population. In contrast to this data, the co-infusion of 4×105 Ad-MSCs mediated a significant increase in the engraftment of LSK cells, an observation that was even more marked when 6×105 Ad-MSCs/mouse were co-infused. No further increments were observed in the group co-infused with 106 Ad-MSCs (Fig. 3a). When analyses were performed at 8 and 12 weeks after transplant, doses of 6×105 and 106 Ad-MSCs still showed improvements in the engraftment of purified LSK cells (see fold increases of engraftment in Fig. 3a and representative absolute values of engraftment in Fig. 3b). These results thus demonstrate that the hematopoietic engraftment effect of Ad-MSCs is dose-dependent. Additionally, our data indicate that relatively low doses of Ad-MSCs can accelerate the engraftment of transplanted LSK cells but that higher Ad-MSC doses are required to improve LSK cell engraftment in later stages post-transplantation.Fig. 3

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.