Mesenchymal Stromal Cells: Current Understanding and Clinical Status

Salem, Husein K.; Thiemermann, Christoph

doi:10.1002/stem.269

Cited by 810 publications

(648 citation statements)

References 126 publications

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“…These endogenous progenitor cells can be mobilized to the PB [1,11,12,15,17,22,36,48,52]. Circulating MSCs, and perhaps other adult stem cells, home to sites of skeletal injury [14,23,29,35,45,54], and increasing the number of adult stem cells at sites of injury aids tissue regeneration [4,8,16,40,43,56] either directly or through trophic effects [5,8,17,53].…”

Section: Introductionmentioning

confidence: 99%

Adult Stem Cell Mobilization Enhances Intramembranous Bone Regeneration: A Pilot Study

McNulty

Virdi

Christopherson

et al. 2012

Clinical Orthopaedics &Amp; Related Research

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Background Stem cell mobilization, which is defined as the forced egress of stem cells from the bone marrow to the peripheral blood (PB) using chemokine receptor agonists, is an emerging concept for enhancing tissue regeneration. However, the effect of stem cell mobilization by a single injection of the C-X-C chemokine receptor type 4 (CXCR4) antagonist AMD3100 on intramembranous bone regeneration is unclear.

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Section: Introductionmentioning

confidence: 99%

Adult Stem Cell Mobilization Enhances Intramembranous Bone Regeneration: A Pilot Study

McNulty

Virdi

Christopherson

et al. 2012

Clinical Orthopaedics &Amp; Related Research

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“…7a, b). 24 MSC-derived VSMC expressed smooth muscle actin alpha (SMAα), calponin, and transgelin at high levels (SM22α; Supplementary Fig. 7c).…”

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confidence: 99%

PDE3A mutations cause autosomal dominant hypertension with brachydactyly

et al. 2015

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All Mendelian hypertension syndromes described to date involve increased sodium reabsorption in the distal nephron. 5 The sole exception is autosomal-dominant hypertension with BDE (HTNB, OMIM #112410), first reported in a Turkish kindred. 2,6 HTNB was linked to chromosome 12p in six unrelated families. 2,7,8 The locus accounts for a ~50 mm Hg mean blood pressure difference at age 50 years. 2 The penetrance is 100% (Fig. 1a). Previously, we reported a rearrangement on chromosome 12p common to all families. 8,9 A linkage study in Chinese hypertensive families without BDE coincided with the HTNB locus, supporting relevance to essential hypertension. 10 Whole-genome sequencing of Turkish family members revealed a heterozygous missense mutation in PDE3A (Gene ID: 5139), a gene encoding a cGMP/cAMP phosphodiesterase with a prominent role in the heart, VSMC, oocytes and platelets. 11 Resequencing of all 48 affected persons in six unrelated families identified six independently clustered heterozygous missense mutations in exon 4 (Fig. 1a, b Supplementary Fig. 1).We detected none of the previously described chromosomal breakpoints on chromosome 12p12.2-12.1, perhaps due to high repetitive content in the breakpoint regions Fig. 2a-c). 4 A haplotype analysis identified a novel recombination that reduced the linkage interval and eliminated an inversion common to all affected individuals in the six families (Fig. 2c). 9 In contrast, the affected mother's haplotype showed co-segregation with the more severe brachydactyly phenotype.PDEs are involved during early stages of osteogenesis. 12 PDE4D mutations have been associated with severe brachydactyly in acrodysostosis. 13,14 In mice, Pde3a was expressed in the developing limbs, consistent with a role during chondrogenesis (Fig. 2d, Supplementary Fig. 3a, b). Chondrogenic downregulation of PTHLH encoding PTHrP was associated with BDE. 15 We also observed PTHLH downregulation in chondrogenically induced fibroblasts from affected persons (Fig. 2e, Supplementary Fig. 3c).We addressed the functional consequences of the identified PDE3A mutations in HeLa cells expressing the six mutations. Forskolin or L-arginine stimulated the adenylate or guanylate cyclases to enhance cellular cAMP or cGMP levels, respectively. 16,17 We detected significantly reduced cAMP levels, consistent with gain-of-function mutations with no change in cGMP levels for the PDE3A mutations ( Supplementary Fig. 4a, b). Three PDE3A isoforms, PDE3A1 (microsomal), PDE3A2 and PDE3A3 (microsomal and cytosolic), have been identified in human myocardium. 18,19 PDE3A3 does not contain the sequence harboring the detected mutations. The predominant isoform in VSMC is PDE3A2. 18,20 To directly elucidate the mutations' effects, we compared the Michaelis-Menten kinetics of cAMPhydrolytic activity for recombinant T445N FLAG-tagged PDE3A1 and PDE3A1-WT and the tagged A2 isoforms purified from transfected cells (Fig. 3a, b, Supplementary Fig. 4d-k). The T445N mutation increased the affinity of both enzyme's isoforms for cAM...

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“…First, MSCs require activation by certain cytokines, for example, IFNg, TNFa, IL-1b, and IL-1a, in order to develop immunosuppressive functions (Ren et al, 2008;Salem and Thiemermann, 2010). This has been demonstrated in an in-vivo model of GvHD, where MSCs were only immunosuppressive after IFNginduced synthesis of nitric oxide (Ren et al, 2008).…”

Section: Discussionmentioning

confidence: 99%

Immune Effects of Mesenchymal Stromal Cells in Experimental Stroke

Scheibe

Ladhoff

Huck

et al. 2012

J Cereb Blood Flow Metab

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Preclinical trials confirmed the potential of mesenchymal stromal cells (MSCs) to improve functional recovery after experimental stroke. Beneficial effects of MSCs are often attributed to their immunosuppressive/immunomodulatory functions. Surprisingly, the influence of MSCs on the immune system after stroke is poorly understood, but requires special consideration because cerebral ischemia is associated with stroke-induced immunodepression that predisposes to bacterial infections with increased mortality. In this study, we intravenously transplanted syngeneic murine bone marrowderived MSCs (mMSCs) into C57BL/6 mice at 6 hours after transient middle cerebral artery occlusion (MCAo; 60 minutes) to investigate the impact of MSCs on stroke-induced immunodepression. Transplantation of syngeneic splenocytes or phosphate-buffered saline (PBS) served as controls. An immune status was determined by flow cytometry on days 3 and 14 after MCAo, which did not reveal any negative effects of cell transplantation on stroke-induced immunodepression. Although our mMSCs were found to exert immunosuppressive effects in vitro, stroke-mediated immune cell dysfunction was not altered by mMSCs in ex-vivo stimulation assays with lipopolysaccharide or concanavalin A. Moreover, systemic inflammatory cytokine levels (interleukin-6, tumor necrosis factora, interferonc, monocyte chemoattractant protein-1) remained unchanged in the sera of mice after cerebral ischemia and cell transplantation. These results reduce safety concerns about MSC administration in ongoing clinical stroke trials.

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Mesenchymal Stromal Cells: Current Understanding and Clinical Status

Cited by 810 publications

References 126 publications

Adult Stem Cell Mobilization Enhances Intramembranous Bone Regeneration: A Pilot Study

Adult Stem Cell Mobilization Enhances Intramembranous Bone Regeneration: A Pilot Study

PDE3A mutations cause autosomal dominant hypertension with brachydactyly

Immune Effects of Mesenchymal Stromal Cells in Experimental Stroke

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