Pericytes of Multiple Organs Do Not Behave as Mesenchymal Stem Cells In Vivo

Guimarães-Camboa, Nuno; Cattaneo, Paola; Sun, Yunfu; Moore-Morris, Thomas; Gu, Yusu; Dalton, Nancy D.; Rockenstein, Edward; Masliah, Eliezer; Peterson, Kirk L.; Stallcup, William B.; Chen, Ju; Evans, Sylvia M.

doi:10.1016/j.stem.2016.12.006

Cited by 414 publications

(380 citation statements)

References 36 publications

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“…Interestingly, pericytes have also been hypothesized to be mesenchymal stem cells in adult tissue (4), however, recent studies using lineage tracing have disproved this theory (5). The current understanding of the role pericytes and their mesenchymal precursors play in adult lung disease, de novo angiogenesis, and vascular remodeling is controversial, as conflicting evidence depicts angiogenesis as both reparative and pathologic (6)(7)(8).…”

Section: Introductionmentioning

confidence: 99%

Disruption of lineage specification in adult pulmonary mesenchymal progenitor cells promotes microvascular dysfunction

Gaskill¹,

Carrier²,

Kropski³

et al. 2017

Journal of Clinical Investigation

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Section: Introductionmentioning

confidence: 99%

Disruption of lineage specification in adult pulmonary mesenchymal progenitor cells promotes microvascular dysfunction

Gaskill¹,

Carrier²,

Kropski³

et al. 2017

Journal of Clinical Investigation

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“…Pericytes have been traced in vivo in different tissues and found to retain their original identity [6,7]. It remains unclear, however, how long and exactly through what mechanisms these pericytes stimulate a host response.…”

mentioning

confidence: 99%

Response to: Mesenchymal Stem Cells: Time to Change the Name!

Windt

Vonk

Saris

2017

Stem Cells Translational Medicine

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With great pleasure, we read the recent Perspective by Arnold Caplan in which he urges that we change the name of mesenchymal stem cells (MSCs) to "medicinal signaling cells" [1]. While a name should not be considered an impediment to scientific progress, it is the underlying expectation of the clinical effect of these cells that may encumber the role of MSCs in the field of regenerative medicine. According to the Cambridge dictionary, a stem cell is defined as "a cell, especially one taken from a person or animal in a very early stage of development that can develop into any other type of cell." Because the main functionality of MSCs in vivo is not multipotency, but rather immunomodulatory and trophic, it is argued that we should not call them stem cells after all.We must admit that, when our group started to work with bone-marrow derived MSCs, we called them mesenchymal stem cells because they were able to differentiate into bone, fat, and cartilage in vitro, or at least express the corresponding markers. In aiming at cartilage regeneration, we mixed chondrocytes and MSCs, with the initial hypothesis that the environment would stimulate MSC differentiation [2]. Different groups demonstrated similar results when mixing these cells and incorrectly concluded it was the MSCs that were responsible for the cartilage tissue regeneration [3]. Soon we came to realize that it was not the MSCs that created reproducible cartilage constructs. MSCs were found to induce chondrocytes and stimulate their chondrogenic capacity [4]. We found that preserving the pericellular matrix of chondrocytes (chondrons) enhanced this interaction with MSCs [2]. We also demonstrated that MSCs did not communicate solely through soluble factors, as direct cell-cell contact through gap junctions played an important role in the cellular crosstalk [4]. We and others showed that MSCs disappeared from cocultures while stimulating tissue regeneration [3,5].In his Perspective, Arnold Caplan neatly describes the evolving insight that MSCs are derived from pericytes. Pericytes have been traced in vivo in different tissues and found to retain their original identity [6,7]. It remains unclear, however, how long and exactly through what mechanisms these pericytes stimulate a host response. For example, while trophic factors excreted by MSCs seem to inhibit scar formation and apoptosis, the role of extracellular vesicle excretion and their amelioration of inflammation is only just recently being explored [8]. Although there is evidence that MSCs can remain traceable after several weeks in vivo, it is unclear how implanted cells behave in the human being [9].Based on our clinical work and supported by the signaling cell hypothesis, we assessed the presence of donor DNA from allogeneic MSCs 12 months after implantation in cartilage defects in the knee [10]. In this first-in-human trial, allogeneic MSCs were mixed with autologous recycled chondrons and implanted within a single surgery. DNA analysis using short tandem repeats confirmed our hypothesis that MSCs...

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“…Both saphenous vein–derived swine cells and hAPCs were negative for the endothelial markers CD31 and VE‐cadherin, and expressed very low levels of CD146, whereas human umbilical vein endothelial cells and sPAECs (positive controls) express all the above antigens (Figure 5E). We also verify the expression of the T‐box family transcription factor Tbx18, which is reportedly selectively expressed by microvascular pericytes and vascular smooth muscle cells in the adult mouse 27. Results confirm that the TBX18 gene is detected by polymerase chain reaction for both cell lines (Ct value hAPCs=24.4 and Ct value sAPCs=26.6, data not shown), with the expression being confirmed at the protein level by Western blot analyses of cell lysates (Figure 5F).…”

Section: Resultsmentioning

confidence: 71%

Transplantation of Allogeneic Pericytes Improves Myocardial Vascularization and Reduces Interstitial Fibrosis in a Swine Model of Reperfused Acute Myocardial Infarction

Alvino

Fernández‐Jiménez

Rodriguez‐Arabaolaza

et al. 2018

JAHA

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BackgroundTransplantation of adventitial pericytes (APCs) promotes cardiac repair in murine models of myocardial infarction. The aim of present study was to confirm the benefit of APC therapy in a large animal model.Methods and ResultsWe performed a blind, randomized, placebo‐controlled APC therapy trial in a swine model of reperfused myocardial infarction. A first study used human APCs (hAPCs) from patients undergoing coronary artery bypass graft surgery. A second study used allogeneic swine APCs (sAPCs). Primary end points were (1) ejection fraction as assessed by cardiac magnetic resonance imaging and (2) myocardial vascularization and fibrosis as determined by immunohistochemistry. Transplantation of hAPCs reduced fibrosis but failed to improve the other efficacy end points. Incompatibility of the xenogeneic model was suggested by the occurrence of a cytotoxic response following in vitro challenge of hAPCs with swine spleen lymphocytes and the failure to retrieve hAPCs in transplanted hearts. We next considered sAPCs as an alternative. Flow cytometry, immunocytochemistry, and functional/cytotoxic assays indicate that sAPCs are a surrogate of hAPCs. Transplantation of allogeneic sAPCs benefited capillary density and fibrosis but did not improve cardiac magnetic resonance imaging indices of contractility. Transplanted cells were detected in the border zone.ConclusionsImmunologic barriers limit the applicability of a xenogeneic swine model to assess hAPC efficacy. On the other hand, we newly show that transplantation of allogeneic sAPCs is feasible, safe, and immunologically acceptable. The approach induces proangiogenic and antifibrotic benefits, though these effects were not enough to result in functional improvements.

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Pericytes of Multiple Organs Do Not Behave as Mesenchymal Stem Cells In Vivo

Cited by 414 publications

References 36 publications

Disruption of lineage specification in adult pulmonary mesenchymal progenitor cells promotes microvascular dysfunction

Disruption of lineage specification in adult pulmonary mesenchymal progenitor cells promotes microvascular dysfunction

Response to: Mesenchymal Stem Cells: Time to Change the Name!

Transplantation of Allogeneic Pericytes Improves Myocardial Vascularization and Reduces Interstitial Fibrosis in a Swine Model of Reperfused Acute Myocardial Infarction

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