Microvesicles Secreted by Nitric Oxide-Primed Mesenchymal Stromal Cells Boost the Engraftment Potential of Hematopoietic Stem Cells

Abstract

Patients with leukemia, lymphoma, severe aplastic anemia, etc. are frequently the targets of bone marrow transplantation, the success of which critically depends on efficient engraftment by transplanted hematopoietic cells (HSCs). Ex vivo manipulation of HSCs to improve their engraftment ability becomes necessary when the number or quality of donor HSCs is a limiting factor. Due to their hematopoiesis-supportive ability, bone marrow-derived mesenchymal stromal cells (MSCs) have been traditionally used as feeder layers for ex vivo expansion of HSCs. MSCs form a special HSC-niche in vivo, implying that signaling mechanisms operative in them would affect HSC fate. We have recently demonstrated that AKT signaling prevailing in the MSCs affect the HSC functionality. Here we show that MSCs primed with nitric oxide donor, Sodium nitroprusside (SNP), significantly boost the engraftment potential of the HSCs co-cultured with them via intercellular transfer of microvesicles (MVs) harboring mRNAs encoding HSC-supportive genes. Our data suggest that these MVs could be used as HSC-priming agents to improve transplantation efficacy. Since both, nitric oxide donors and MSCs are already in clinical use; their application in clinical settings may be relatively straight forward. This approach could also be applied in regenerative medicine protocols. Stem Cells 2019;37:128–138

Mesenchymal stromal cell‐derived extracellular vesicles as cell‐free biologics for the ex vivo expansion of hematopoietic stem cells

“…Our group has shown in particular that MVs isolated from MSCs that have silenced AKT boost the engrafting capacity of HSCs interacting with them, while those isolated from stromal cells with a constitutively active AKT negatively affect the functionality of HSCs (Singh et al, 2016). In another study, we found that MVs isolated from MSCs treated with NO donors significantly improves the engraftment ability of HSCs (Jalnapurkar et al, 2018). MVs isolated from young and naive MSCs rejuvenate old HSCs and increase their engraftment ability via the transfer of MVs harboring autophagy‐related mRNAs (Kulkarni et al, 2019).…”

“…Additionally, we have shown that NO increases the engrafting ability of juvenile HSCs, but has an adverse effect on adult HSC's engrafting ability (Jalnapurkar et al, 2016). Furthermore, we saw that MSCs primed with a donor of NO, SNP, significantly increased the engraftment potential of HSCs cocultured with them through the intercellular transfer of MVs containing mRNAs encoding HSC‐supporting genes (Jalnapurkar et al, 2018).…”

“…MSC‐derived EVs have gained considerable interest as an effective cell‐free treatment as they can reiterate the therapeutic and regenerative effects of MSCs (de Jong et al, 2014; Rani et al, 2015). Several studies by our group have demonstrated that HSCs can be expanded ex vivo using MSC‐derived EVs (Xie et al, 2016; Jalnapurkar et al, 2018; Kulkarni et al, 2018, 2019). We have shown that the content of the cargo carried by the EVs depends heavily on the age of the MSCs and also on the signaling mechanisms prevailing in them, which further affects the fate of the HSCs exposed to these EVs (Singh et al, 2016; Kulkarni et al, 2018).…”

“…EVs from young MSCs, for example, have been shown to rejuvenate old HSCs, thereby improving their engraftment capacity (Kulkarni et al, 2018). In yet another study from our laboratory, it was demonstrated that EVs derived from MSCs treated with sodium nitroprusside (SNP), significantly boosted the engraftment potential of HSCs (Jalnapurkar et al, 2018). It can, therefore, be hypothesized that EVs derived from modulated MSCs could be used for priming HSCs to improve their transplantation efficiency (Jalnapurkar et al, 2018).…”

“…In yet another study from our laboratory, it was demonstrated that EVs derived from MSCs treated with sodium nitroprusside (SNP), significantly boosted the engraftment potential of HSCs (Jalnapurkar et al, 2018). It can, therefore, be hypothesized that EVs derived from modulated MSCs could be used for priming HSCs to improve their transplantation efficiency (Jalnapurkar et al, 2018). On the basis of results reported in the literature coupled with our data, EVs seem to be a promising candidate for expanding HSCs for therapeutic applications.…”