Targeting of Deciduous Tooth Pulp Stem Cell–Derived Extracellular Vesicles on Telomerase-Mediated Stem Cell Niche and Immune Regulation in Systemic Lupus Erythematosus

Abstract

Systemic transplantation of stem cells from human exfoliated deciduous teeth (SHED) is used to treat systemic lupus erythematosus (SLE)–like disorders in MRL/lpr mice. However, the mechanisms underlying the SHED-based therapy remain unclear. In this study, we hypothesized that trophic factors within SHED-releasing extracellular vesicles (SHED-EVs) ameliorate the SLE-like phenotypes in MRL/lpr mice. SHED-EVs were isolated from the culture supernatant of SHED. SHED-EVs were treated with or without RNase and systemically administered to MRL/lpr mice. Subsequently, recipient bone marrow mesenchymal stem cells (BMMSCs) isolated from SHED-EV–administered MRL/lpr mice were examined for the in vitro and in vivo activity of hematopoietic niche formation and immunoregulation. Furthermore, the recipient BMMSCs were secondarily transplanted into MRL/lpr mice. The systemic SHED-EV infusion ameliorated the SLE-like phenotypes in MRL/lpr mice and improved the functions of recipient BMMSCs by rescuing Tert mRNA-associated telomerase activity, hematopoietic niche formation, and immunoregulation. The secondary transplantation of recipient BMMSCs recovered the immune condition and renal functions of MRL/lpr mice. The RNase treatment depleted RNAs, such as microRNAs, within SHED-EVs, and the RNA-depleted SHED-EVs attenuated the benefits of SHED-EVs in MRL/lpr mice. Collectively, our findings suggest that SHED-secreted RNAs, such as microRNAs, play a crucial role in treating SLE by targeting the telomerase activity of recipient BMMSCs.

A New Target of Dental Pulp-Derived Stem Cell-Based Therapy on Recipient Bone Marrow Niche in Systemic Lupus Erythematosus

“…When hDPSCs are co-cultured with T lymphocytes activated with plate bounded anti-CD3 and soluble anti-CD28 antibodies, hDPSCs induce the differentiation of CD4 + CD25 + Foxp3 + regulatory T cells (Tregs) and the release of interleukin 10 (IL-10), following stimulation with transforming growth factor-beta (TGFB)/IL-2. hDPSCs also suppress the differentiation of CD4 + IL - 17 + interferon-gamma − (IFNG − ) T helper 17 (Th17) cells and IL-17 release upon stimulation with TGFB/IL-6 [ 15 , 19 , 35 ]. Interestingly, hDPSCs express both Fas and FasL [ 36 ].…”

“…hDPSCs could potentially modulate the proliferation, function, and death of T lymphocytes. Recently, due to their potent immunomodulatory properties, hDPSCs have been investigated for the treatment of SLE, experimental colitis, and asthma [ 15 , 35 , 36 ].…”

“…Therefore, this dynamic integration of bone marrow-like hematopoietic tissue compartments post-BMMSC transplantation occurs at least in part through intercellular communication between donor BMMSCs and recipient hematopoietic cells. Thus, subcutaneous transplantation of BMMSCs is a reliable method that can be used to investigate BMMSC-mediated hematopoietic reconstruction and function [ 35 , 63 ]. Since bone marrow also functions as a primary lymphoid organ, niche-forming BMMSCs may also contribute to the regulation of lymphocyte production and differentiation.…”

“…Eight weeks after implantation, hDPSC- lpr -BMMSCs restored the formation of de novo bone marrow-like hematopoietic tissue components. hDPSC- lpr -BMMSCs further aided the accumulation of hematopoietic cells, including Sca-1-, c-Kit-, and CD45-positive cells in the implants, compared to the lpr -BMMSCs [ 35 ]. In comparison to lpr -BMMSCs, hDPSC- lpr -BMMSCs also improved both in vitro formation of hematopoietic colonies and in vitro immunomodulatory functions by decreasing Th17 cells, increasing Tregs, and enhancing CD4 + AnnexinV + 7AAD + apoptotic T lymphocytes [ 35 ].…”

“…hDPSC- lpr -BMMSCs further aided the accumulation of hematopoietic cells, including Sca-1-, c-Kit-, and CD45-positive cells in the implants, compared to the lpr -BMMSCs [ 35 ]. In comparison to lpr -BMMSCs, hDPSC- lpr -BMMSCs also improved both in vitro formation of hematopoietic colonies and in vitro immunomodulatory functions by decreasing Th17 cells, increasing Tregs, and enhancing CD4 + AnnexinV + 7AAD + apoptotic T lymphocytes [ 35 ]. When hDPSC- lpr -BMMSCs and lpr -BMMSCs were systemically infused into MRL/ lpr mice, hDPSC- lpr -BMMSCs ameliorated SLE-like disorders, including abnormal levels of serum autoantibodies, such as anti-dsDNA IgG, anti-dsDNA IgM, and ANA.…”