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Co?transplantation of tonsil?derived mesenchymal stromal cells in bone marrow transplantation promotes thymus regeneration and T cell diversity following cytotoxic conditioning.

ABSTRACT: Bone marrow (BM) transplantation (BMT) represents a curative treatment for various hematological disorders. Prior to BMT, a large amount of the relevant anticancer drug needed to be administered to eliminate cancer cells. However, during this pre?BMT cytotoxic conditioning regimen, hematopoietic stem cells in the BM and thymic epithelial cells were also destroyed. The T cell receptor (TCR) recognizes diverse pathogen, tumor and environmental antigens, and confers immunological memory and self?tolerance. Delayed thymus reconstitution following pre?BMT cytotoxic conditioning impedes de novo thymopoiesis and limits T cell?mediated immunity. Several cytokines, such as RANK ligand, interleukin (IL)?7, IL?22 and stem cell factor, were recently reported to improve thymopoiesis and immune function following BMT. In the present study, it was found that the co?transplantation of tonsil?derived mesenchymal stromal cells (T?MSCs) with BM?derived cells (BMCs) accelerated the recovery of involuted thymuses in mice following partial pre?BMT conditioning with busulfan?cyclophosphamide treatment, possibly by inducing FMS?like tyrosine kinase 3 ligand (FLT3L) and fibroblast growth factor 7 (FGF7) production in T?MSCs. The co?transplantation of T?MSCs with BMCs also replenished the CD3+ cell population by inhibiting thymocyte apoptosis following pre?BMT cytotoxic conditioning. Furthermore, T?MSC co?transplantation improved the recovery of the TCR repertoire and led to increased thymus?generated T cell diversity.

SUBMITTER: Choi DW

PROVIDER: S-EPMC7387097 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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Co‑transplantation of tonsil‑derived mesenchymal stromal cells in bone marrow transplantation promotes thymus regeneration and T cell diversity following cytotoxic conditioning.

Choi Da-Won DW Cho Kyung-Ah KA Lee Hyun-Ji HJ Kim Yu-Hee YH Woo Kyong-Je KJ Park Joo-Won JW Ryu Kyung-Ha KH Woo So-Youn SY

International journal of molecular medicine 20200624 3

Bone marrow (BM) transplantation (BMT) represents a curative treatment for various hematological disorders. Prior to BMT, a large amount of the relevant anticancer drug needed to be administered to eliminate cancer cells. However, during this pre‑BMT cytotoxic conditioning regimen, hematopoietic stem cells in the BM and thymic epithelial cells were also destroyed. The T cell receptor (TCR) recognizes diverse pathogen, tumor and environmental antigens, and confers immunological memory and self‑to ...[more]

PMID: 32582998

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Project description:Current wound healing models generally employ full-thickness or irregular split wounds. Consequently, assessing the type of healing at varying wound depths and determining the deepest level at which wounds can regenerate has been a challenge. We describe a wound model that allows assessment of the healing process over a continuous gradient of wound depth, from epidermal to full-thickness dermal loss. Further, we investigate whether green fluorescent protein-labeled bone marrow mesenchymal stem cells (BM-MSCs/GFP) transplantation could regenerate deeper wounds that might otherwise lead to scar formation. A wound gradient was created on the back of 120 Sprague Dawley rats, which were randomized into the BM-MSCs/GFP and control group. These were further subdivided into 6 groups where terminal biopsies of the healing wounds were taken at days 1, 3, 5, 7, 14, and 21 post-operatively. At each observed time point, the experimental animals were anesthetized and photographed, and depending on the group, the animals euthanized and skin taken for rapid freezing, haemotoxylin and eosin staining, and vascular endothelial growth factor (VEGF) immunohistochemistry. We found the deepest layer to regenerate in the control group was at the level of the infundibulum apex, while in the BM-MSCs/GFP group this was deeper, at the opening site of sebaceous duct at hair follicle in which had the appearance of normal skin and less wound contraction than the control group (P value less than .05). The expression of VEGF in BM-MSCs/GFP group was higher than that in control group (P value less than .05). The number of vessels increased from 2.5 ± 0.2/phf of control group to 5.0 ± 0.3/phf of BM-MSCs/GFP (P value less than .05). The progressively deepening wound model we described can identify the type of wound repair at increasing depths. Further, topical transplantation of BM-MSCs/GFP significantly improved regeneration of deeper wounds from infundibulum apex (maximum depth of control group regeneration) to the opening site of sebaceous duct at hair follicle level.

Project description:BackgroundConnective tissue progenitors (CTPs) from native bone marrow (BM) or their culture-expanded progeny, often referred to as mesenchymal stem/stromal cells, represents a promising strategy for treatment of cartilage injuries. But the cartilage regeneration capacity of these cells remains unpredictable because of cell heterogeneity.HypothesisThe harvest technique of BM may highly influence stem cell heterogeneity and, thus, cartilage formation because these cells have distinct spatial localization within BM from the same bone.Study designControlled laboratory study.MethodsCTPs obtained from the femur of patients undergoing total hip replacement by 2 harvest techniques-BM aspiration and BM collection-after bone rasping were immunophenotyped by flow cytometry and evaluated for chondrogenic ability. The spatial localization of different CTP subsets in BM was verified by immunohistochemistry.ResultsCells from the BM after rasping were significantly more chondrogenic than the donor-matched aspirate, whereas no notable difference in their osteogenic or adipogenic potential was observed. The authors then assessed whether distinct immunophenotypically defined CTP subsets were responsible for the different chondrogenic capacity. Cells directly isolated from BM after rasping contained a higher percentage (mean, 7.2-fold) of CD45-CD271+CD56+ CTPs as compared with BM aspirates. The presence of this subset in the harvested BM strongly correlated with chondrogenic ability, showing that CD271+CD56+ cells are enriched in chondroprogenitors. Furthermore, evaluation of these CTP subsets in BM revealed that CD271+CD56+ cells were localized in the bone-lining regions whereas CD271+CD56- cells were found in the perivascular regions. Since the iliac crest remains a frequent site of BM harvest for musculoskeletal regeneration, the authors also compared the spatial distribution of these subsets in trabeculae of femoral head and iliac crest and found CD271+CD56+ bone-lining cells in both tissues.ConclusionChondrogenically distinct CTP subsets have distinct spatial localization in BM; hence, the harvest technique of BM determines the efficiency of cartilage formation.Clinical relevanceThe harvest technique of BM may be of major importance in determining the clinical success of BM mesenchymal stem/stromal cells in cartilage repair.

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Co?transplantation of tonsil?derived mesenchymal stromal cells in bone marrow transplantation promotes thymus regeneration and T cell diversity following cytotoxic conditioning.

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Co‑transplantation of tonsil‑derived mesenchymal stromal cells in bone marrow transplantation promotes thymus regeneration and T cell diversity following cytotoxic conditioning.

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