Clonogenic multipotent stem cells in human adipose tissue differentiate into functional smooth muscle cells

Rodríguez, Larissa V.; Alfonso, Zeni; Zhang, Rong; Leung, Jessica C.; Wu, Benjamin M.; Ignarro, Louis J.

doi:10.1073/pnas.0604850103

Cited by 281 publications

(241 citation statements)

References 39 publications

(48 reference statements)

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“…Further work is needed to conclusively exclude this possibility in vivo. Even with this caveat, the present validation of MDSC conversion into SMCs supports the use of MDSCs for ageing-related ED, in a fashion similar to their postulated use for the regeneration of SMCs in the bladder and urethra [25,26,31], albeit if the latter was essentially based on αSMA detection. The present results appear to be the first to show in vitro the conversion of MDSCs into SMCs based on a true SMC marker, as a previous study used only αSMA [30].…”

Section: Discussionmentioning

confidence: 76%

“…To date, only a few studies of stem cell implantation in experimental models of ED, to repair either nerves or smooth muscle in the corpora, have been conducted [20][21][22][23], although stem cells are also being investigated for the repair of other urogenital organs, such as the bladder, urethra, and kidney [24][25][26][27]. The first study in the penis [20] was based on the injection of rat embryonic stem cells modified ex vivo to express brain-derived nerve growth factor into the corpora cavernosa in a rat model of cavernosal nerve damage.…”

Section: Introductionmentioning

confidence: 99%

“…MDSCs can be prepared from skeletal muscle biopsies, more accessible for autologous transplants than bone marrow, and as such do not pose the immunogenic risks of embryonic stem cells [28]. MDSCs have been claimed to generate SMCs in vitro [30], albeit the SMC characterization was not performed with true SMC markers, such as calponin or smoothelin and particularly in vivo after implantation in the urethra in a rat model of stress urinary incontinence [26,31]. Intrapenile injection of MDSCs also improved erectile function in a bilateral cavernosal nerve resection rat model of ED [23], but as the objective was to improve nerve regeneration after bilateral cavernosal nerve resection, no studies on MDSC differentiation into corporal SMCs were performed.…”

Section: Introductionmentioning

confidence: 99%

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Effect of muscle‐derived stem cells on the restoration of corpora cavernosa smooth muscle and erectile function in the aged rat

et al. 2008

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OBJECTIVETo determine whether skeletal muscle‐derived stem cells (MDSCs) convert into smooth muscle cells (SMCs) both in vitro and in vivo, and in so doing ameliorate the erectile dysfunction (ED) of aged rats, and whether endogenous stem cells are present in the rat corpora cavernosa.MATERIALS AND METHODSMDSCs were obtained from mouse muscle, and shown by immunocytochemistry for α‐smooth muscle actin (αSMA) to originate in vitro in myofibroblasts and SMCs, discriminating SMCs by calponin 1 expression. In vivo these MDSCs, labelled with 4′,6‐diamidino‐2‐phenylindole, were implanted into the corpora cavernosa of young adult (5‐month old) and aged (20‐month old) rats for 2 and 4 weeks. Histological changes were assessed by immunohistochemistry and quantitative Western blot. Functional changes were determined by electrical field stimulation (EFS) of the cavernosal nerve.RESULTSThe exogenous cells replicated and converted into SMCs, as shown in corporal tissue sections by confocal immunofluorescence microscopy for proliferating cell nuclear antigen (PCNA), αSMA, and smoothelin, and also by Western blot for αSMA and PCNA. MDSC differentiation was confirmed by the activation of the αSMA promoter‐linked β‐galactosidase in transfected cells, both in vitro and after implantation in the corpora. Putative endogenous stem cells were shown in corporal tissue sections and Western blots by detecting CD34 and a possible Sca1 variant. EFS showed that implanted MDSCs raised in aged rats the maximal intracavernosal pressure/mean arterial pressure levels above (2 weeks) or up to (4 weeks) those of young adult rats.CONCLUSIONSMDSCs implanted into the corpora cavernosa of aged rats converted into SMCs and corrected ED, and endogenous cells expressing stem cell markers were also found in untreated tissue. This suggests that exogenous stem cell implantation and/or endogenous stem cell modulation might be viable therapeutic approaches for ageing‐related ED.

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Section: Discussionmentioning

confidence: 76%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Effect of muscle‐derived stem cells on the restoration of corpora cavernosa smooth muscle and erectile function in the aged rat

et al. 2008

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“…4 MSC-like cells have since been isolated from various tissues and are loosely defined by adherence to tissue culture plastic, the combinatorial expression of numerous surface markers (most commonly CD29, CD73, CD105, CD54, Stro-1, and CD44), 5 and their capacity to differentiate into multiple lineages, such as osteoblasts, chondrocytes, adipocytes, and myoblasts. 6 Recent publications have validated the use of human MSCs (hMSCs) isolated from adipose tissues as a source for generating mature SMCs in vitro, 7,8 but the molecular regulation of this process is only partly understood.…”

mentioning

confidence: 99%

A Differentiation-Based MicroRNA Signature Identifies Leiomyosarcoma as a Mesenchymal Stem Cell-Related Malignancy

Danielson

Menéndez

Attolini

et al. 2010

The American Journal of Pathology

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Smooth muscle (SM) is a spontaneously contractile tissue that provides physical support and function to organs such as the uterus. Uterine smooth musclerelated neoplasia comprise common well-differentiated benign lesions called leiomyomas (ULM), and rare, highly aggressive and pleomorphic tumors named leiomyosarcomas (ULMS). MicroRNAs (miRNAs) are small non-coding RNAs that play essential roles in normal cellular development and tissue homeostasis that can be used to accurately subclassify different tumor types. Here, we demonstrate that miRNAs are required for full smooth muscle cell (SMC) differentiation of bone marrow-derived human mesenchymal stem cells (hMSCs). We also report a miRNA signature associated with this process. Moreover, we show that this signature, along with miRNA profiles for ULMS and ULM, are able to subclassify tumors of smooth muscle origin along SM differentiation. Using multiple computational analyses, we determined that ULMS are more similar to hMSCs as opposed to ULM, which are linked with more mature SMCs and myometrium. Furthermore, a comparison of the SM differentiation and ULMS miRNA signatures identified miRNAs strictly associated with SM maturation or transformation, as well as those modulated in both processes indicating a possible dual role. These results support separate origins and/or divergent transformation pathways for ULM and ULMS , resulting in drastically different states of differentiation. In summary , this work expands on our knowledge of the regulation of SM differentiation and sarcoma pathogenesis. (Am J Pathol 2010, 177:908 -917;

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“…ASCs can be directed to differentiate into vascular endothelial cells [5,[10][11][12] and smooth muscle-like cells [13,14] and contribute to repair in ischemic tissue. ASCs also promote mobilization of bone marrow endothelial progenitors that also participate in neovascularization [15,16].…”

Section: Introductionmentioning

confidence: 99%

Influence of Donor Age and Passage Number on Angiogenic Activity in Human Adipose-Derived Stem Cell-Conditioned Media

Nakamura¹,

Kazama²,

Nagaoka³

et al. 2015

J Stem Cell Res Ther

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Introduction: Adipose-derived stem/stromal cells (ASCs) are considered a promising cell source for therapeutic angiogenesis because the cells can be prepared following a minimally invasive procedure and because they secrete a variety of angiogenic cytokines. In the present study, the influence of donor age and passage number on angiogenic activity of ASC-conditioned media (ASC-CM) was examined.Methods: Human ASCs (donor age, 5 months to 82 years; n = 10) were cultured, and ASC-CM were collected at passages 2, 4, and 6. The angiogenic activity of ASC-CM was evaluated with the tube formation assay using a system in which human umbilical vein endothelial cells (HUVECs) and fibroblasts were co-cultured. The concentrations of vascular endothelial growth factor-A (VEGF-A) and hepatocyte growth factor (HGF) in each ASC-CM were measured using an enzyme-linked immunosorbent assay. Results:A donor age over 60 years affected the proliferative capacity of ASCs at passage 4 and later. ASC-CM significantly enhanced HUVEC tube formation, and this response was not influenced by donor age. ASC-CM at passage 6 showed a lower tube formation capacity compared to ASC-CM at passage 4, although the capacity was still equivalent to the positive control (medium containing10 ng/mL VEGF-A). A donor age over 26 years affected VEGF-A but not HGF levels in ASC-CM, although we found no direct correlation between VEGF-A/HGF levels and the tube formation capacity. Conclusion:Our results demonstrate a passage number-dependent but a donor age-independent decline in the angiogenic activity of ASC-CM.

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Clonogenic multipotent stem cells in human adipose tissue differentiate into functional smooth muscle cells

Cited by 281 publications

References 39 publications

Effect of muscle‐derived stem cells on the restoration of corpora cavernosa smooth muscle and erectile function in the aged rat

Effect of muscle‐derived stem cells on the restoration of corpora cavernosa smooth muscle and erectile function in the aged rat

A Differentiation-Based MicroRNA Signature Identifies Leiomyosarcoma as a Mesenchymal Stem Cell-Related Malignancy

Influence of Donor Age and Passage Number on Angiogenic Activity in Human Adipose-Derived Stem Cell-Conditioned Media

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