scholarly journals CD44 fucosylation on bone marrow-derived mesenchymal stem cells enhances homing and promotes enteric nervous system remodeling in diabetic mice

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Huiying Shi ◽  
Chen Jiang ◽  
Hailing Yao ◽  
Yurui Zhang ◽  
Qin Zhang ◽  
...  
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Nervous System ◽  
Mesenchymal Stem Cells ◽  
Gastrointestinal Tract ◽  
Enteric Nervous System ◽  
Gastrointestinal Motility ◽  
Bioluminescent Imaging ◽  
Diabetic Mice ◽  
Selectin Ligand

Abstract Background Diabetes can cause extensive enteric nervous system (ENS) injuries and gastrointestinal motility disorder. In developing possible treatments, researchers have engaged in tissue regeneration engineering with the very promising bone marrow-derived mesenchymal stem cells (BMSCs). However, BMSCs have poor homing ability to the targeted tissues after intravenous injection. Thus, we aimed to investigate whether enhancing the expression of E-selectin ligand on BMSCs could improve their homing ability and subsequently influence their role in ENS remodeling in diabetic mice. Methods First, we constructed the fucosylation modification of CD44 on BMSCs through a fucosyltransferase VII (FTVII) system to generate a Hematopoietic Cell E-/L-selectin Ligand (HCELL) property, a fucosylated sialyllactosaminyl glycovariant of CD44 that potently binds E-selectin. Next, FTVII-modified and unmodified BMSCs labeled with green fluorescent protein (GFP) were injected into diabetic mice through the tail vein to compare their homing ability to the gastrointestinal tract and their effect on ENS remodeling, respectively. A bioluminescent imaging system was used to evaluate the homing ability of GFP-labeled BMSCs with and without FTVII modification, to the gastrointestinal tract. Gastrointestinal motility was assessed by gastrointestinal transient time, defecation frequency, stool water content and colon strips contractility. Immunofluorescence staining and western blotting were used to assess the expression levels of protein gene product 9.5 (PGP9.5), glial fibrillary acidic protein (GFAP) and glial cell line-derived neurotrophic factor (GDNF). Results The FTVII-mediated α(1,3)-fucosylation modification of CD44 on BMSCs generated a HCELL property. Bioluminescent imaging assays showed that FTVII-modified BMSCs had enhanced homing ability to gastrointestinal tract, mainly to the colon, 24 h after injection through the tail vein. Compared with diabetic mice, FTVII-modified BMSCs significantly promoted the gastrointestinal motility and the ENS remodeling, including intestinal peristalsis (P < 0.05), increased feces excretion (P < 0.05) and the water content of the feces (P < 0.05), restored the spontaneous contraction of the colon (P < 0.05), and upregulated the protein expression levels of PGP9.5 (P < 0.01), GFAP (P < 0.001), and GDNF (P < 0.05), while unmodified BMSCs did not (P > 0.05). Conclusions CD44 fucosylation modification on murine BMSCs promotes homing ability to the gastrointestinal tract and ENS remodeling in diabetic mice.

Bone marrow mesenchymal stem cells promote the repair of islets from diabetic mice through paracrine actions

2014 ◽  
Vol 388 (1-2) ◽  
pp. 41-50 ◽  
Author(s):  
Xiaodong Gao ◽  
Lujun Song ◽  
Kuntang Shen ◽  
Hongshan Wang ◽  
Mengjia Qian ◽  
...  
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Mesenchymal Stem Cells ◽  
Diabetic Mice ◽  
Marrow Mesenchymal Stem Cells ◽  
Paracrine Actions

Noncellular Niche Influences: Nervous System Mediators, Metabolic Mediators, and Hypoxia/Oxidative Stress

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. SCI-26-SCI-26
Author(s):  
Simón Méndez-Ferrer
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Nervous System ◽  
Mesenchymal Stem Cells ◽  
Myeloproliferative Neoplasms ◽  
Sympathetic Nerves ◽  
Leukemic Cells ◽  
Hematopoietic Stem ◽  
Hsc Niche ◽  
Central Pacemaker

Hematopoietic stem cells (HSCs) traffic between bone marrow and circulation, what allows for life-saving clinical transplantation. Our previous work has shown that HSC numbers in blood follow circadian oscillations that are regulated by the central pacemaker in the brain, which reaches bone marrow nestin+ mesenchymal stem cells through peripheral sympathetic nerves. In the perinatal bone marrow, HSC-niche forming mesenchymal stem cells might be different from those that form the skeleton and some of them might be neural crest-derived, like peripheral neurons and supporting glial cells. Thus, tight regulation of the bone marrow stem-cell niche in vertebrates might build upon developmental relationships of its cellular components. We have found recently that cholinergic nerves regulate HSC maintenance, proliferation and migration in divergent niches. We will present unpublished evidence of how both branches of the autonomic nervous system cooperate to regulate HSC maintenance and function in spatially and temporally distinct niches. Moreover, we have shown recently that damage to this regulatory network is essential for the manifestation of myeloproliferative neoplasms. In these diseases, previously thought to be driven solely by mutated HSCs, protecting the HSC niche might represent a novel therapeutic strategy. Patients with myeloproliferative neoplasms have a higher risk of developing acute leukemia. However, at this stage, leukemic cells might be less sensitive to the normal control by the microenvironment and, instead, acute myelogenous leukemic cells might transform the bone marrow niches to support their own survival. We will discuss potential contributions of HSC niches to myeloproliferative neoplasms and MLL-AF9-driven acute myeloid leukemia. Disclosures Off Label Use: Potential use of selective estrogen receptor modulators and beta3-adrenergic agonists in myeloproliferative neoplasms.

Mesenchymal Stem Cells, Regulated by the Sympathetic Nervous System, Form the Hematopoietic Stem Cell Niche

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 4-4 ◽  
Author(s):  
Simon Mendez-Ferrer ◽  
Grigori N. Enikolopov ◽  
Sergio Lira ◽  
Paul S. Frenette
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Nervous System ◽  
Mesenchymal Stem Cells ◽  
Sympathetic Nervous System ◽  
Adrenergic Receptor ◽  
Intermediate Filament Protein ◽  
Hematopoietic Stem ◽  
Hsc Niche ◽  
Sympathetic Nervous

Abstract The identity of mesenchymal stem cells (MSCs) and their relationship to hematopoietic stem cells (HSCs) remain poorly defined. In addition, there are discrepancies regarding the cellular constituents of the HSC niche, with studies suggesting a role for bone-lining osteoblasts, and other data implicating sinusoidal endothelial and adventitial reticular cells. Previous work from our group has demonstrated that the sympathetic nervous system (SNS) is critical for both physiological and enforced egress of HSCs from the bone marrow (BM). HSC mobilization induced by G-CSF requires signals from the SNS (Katayama et al. 2006; Cell124:407–21). Physiological release of HSCs into the bloodstream follows circadian oscillations governed by the molecular clock and triggered by cyclical norepinephrine secretion by the SNS in the BM, activation of the β3-adrenergic receptor (encoded in Adrb3), degradation of Sp1 transcription factor and downregulation of Cxcl12 (Mendez-Ferrer et al. 2008; Nature452:442–7). Here, we have identified the cell targeted by the SNS in the BM as a perivascular stromal cell expressing Nestin, an intermediate filament protein characteristic of neuroectoderm-derived stem cells. Using transgenic mice expressing GFP under the regulatory elements of the Nestin promoter, we show that virtually all catecholaminergic fibers in the BM are associated with Nestin+ cells, which represent 4.0 ± 0.6% of BM CD45− cells and 0.08 ± 0.01% of total BM nucleated cells, as determined by FACS analyses. Quantitative real-time PCR (QPCR) analyses have revealed a ~30-fold higher expression of the gene encoding the chemokine CXCL12 in Nestin+ cells than in the rest of BM CD45− cells, whereas Adrb3 was exclusively expressed in Nestin+ cells and not detectable in Nestin− CD45− cells. Detailed immunofluorescence analyses of the spatial distribution of HSCs in longitudinal BM sections revealed that 60% of CD150+ CD48−/Lineage− cells were directly attached to Nestin+ cells, and 90% of HSCs were located within 5 cell diameters from Nestin+ cells in the endosteal or sinusoidal regions of the BM (n=30). In long-term BM cultures, Nestin+ cells were rare, but located near HSCs/progenitors-enriched cobblestone-forming areas. BM Nestin+ cells were associated with HSCs not only physically but also functionally, because core HSC retention signals (Cxcl12, Kitl, Vcam1, Angpt1, Il7) were highly expressed by Nestin+ cells and significantly downregulated during G-CSF-induced mobilization, whereas the expression of the same genes was significantly lower and was not downregulated by G-CSF in Nestin− CD45− cells, as measured by QPCR. A non-selective β- or a selective β3-adrenergic receptor agonist also downregulated these core HSC retention genes, underscoring the role of the SNS in regulating HSC adhesion in the BM niche. Cell sorting of Nestin+ CD45− and Nestin− CD45− cells revealed that all the mesenchymal progenitor activity of the bone marrow (CFU-F) was contained in the Nestin+ cell fraction. Further, Nestin+ cells could robustly differentiate into osteoblasts and adipocytes. Lineage-tracing studies using a Nestin-CRE transgenic line bred to R26R reporter mice have confirmed the contribution of Nestin+ cells to osteoblasts and chondrocytes during development. G-CSF, which induces proliferation of hematopoietic cells in the BM at the expense of non-hematopoietic lineages, significantly downregulated markers of osteoblastic and adipogenic differentiation in BM Nestin+ CD45− cells but not in Nestin− CD45− cells. By contrast, daily administration of parathyroid hormone over five weeks, a treatment previously shown to expand both the osteoblastic and HSC pools, induced proliferation of Nestin+ cells and favored their differentiation into Col1a1-LacZ+ osteoblasts. Finally, we have found that Nestin+ CD45− cells, but not Nestin− CD45− cells, can form self-renewing spheres in clonal density culture, with a frequency similar to other neural crest-derived stem cells. After two weeks in culture, clonal spheres showed spontaneous multilineage differentiation into adipocytes and Col1a1-LacZ+ osteoblasts. Altogether, these results suggest that the HSC niche is composed of a heterotypic MSC-HSC pairing that is tightly regulated by the SNS. This association may reconcile divergent views regarding the vascular and osteoblastic locations of the HSC niche, and its regulation by the SNS might explain the crosstalk between hematopoietic and mesenchymal lineages in the BM during health and disease.

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