Mesenchymal Stem/Stromal Cells in Regenerative Medicine: Can Preconditioning Strategies Improve Therapeutic Efficacy

Schäfer, Richard; Spohn, Gabriele; Baer, Patrick C.

doi:10.1159/000447458

Cited by 107 publications

(130 citation statements)

References 120 publications

(161 reference statements)

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“…One promising therapeutic strategy is enhancing the release of a specific paracrine regenerative factor from stem cells by overexpressing it through genetic engineering (108). In agreement with this hypothesis, overexpression of VEGF in MSCs enhanced stem cell-mediated therapeutic efficacy in neural and cardiac repair (126), and intracerebral transplantation of BDNF gene-modified MSCs 1 day after middle cerebral artery occlusion promoted functional recovery and reduced infarct sizes in rats (127).…”

Section: Genetic Engineering Of Stem Cellsmentioning

confidence: 78%

“…There is growing evidence that in vitro preconditioning of MSCs can optimize their paracrine potency and thus their therapeutic potential (82,(108)(109)(110). Preconditioning of MSCs includes exposure of in vitro MSCs to hypoxic or anoxic conditions (111-114); e.g., the addition of growth factors such as epidermal growth factor (115), glial cell-derived neurotrophic factor (116) (122), deferoxamine (123), or diazoxide (124).…”

Section: Preconditioning Of Stem Cellsmentioning

confidence: 99%

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Strategies to enhance paracrine potency of transplanted mesenchymal stem cells in intractable neonatal disorders

et al. 2017

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Mesenchymal stem cell (MSC) transplantation represents the next breakthrough in the treatment of currently intractable and devastating neonatal disorders with complex multifactorial etiologies, including bronchopulmonary dysplasia, hypoxic ischemic encephalopathy, and intraventricular hemorrhage. Absent engraftment and direct differentiation of transplanted MSCs, and the "hit-and-run" therapeutic effects of these MSCs suggest that their pleiotropic protection might be attributable to paracrine activity via the secretion of various biologic factors rather than to regenerative activity. The transplanted MSCs, therefore, exert their therapeutic effects not by acting as "stem cells," but rather by acting as "paracrine factors factory." The MSCs sense the microenvironment of the injury site and secrete various paracrine factors that serve several reparative functions, including antiapoptotic, anti-inflammatory, antioxidative, antifibrotic, and/or antibacterial effects in response to environmental cues to enhance regeneration of the damaged tissue. Therefore, the therapeutic efficacy of MSCs might be dependent on their paracrine potency. In this review, we focus on recent investigations that elucidate the specifically regulated paracrine mechanisms of MSCs by injury type and discuss potential strategies to enhance paracrine potency, and thus therapeutic efficacy, of transplanted MSCs, including determining the appropriate source and preconditioning strategy for MSCs and the route and timing of their administration.

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Section: Genetic Engineering Of Stem Cellsmentioning

confidence: 78%

Section: Preconditioning Of Stem Cellsmentioning

confidence: 99%

Strategies to enhance paracrine potency of transplanted mesenchymal stem cells in intractable neonatal disorders

et al. 2017

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“…Although cultured MSCs have been shown to exhibit remarkable immunosuppressive capabilities, some studies have also pointed out that the immunoregulatory properties of MSCs may depend on culture conditions and on local microenvironment changes . If brain MPCs behave in a similar manner to MSCs, it may be suggested that MPCs in the brain of MS patients alter their phenotype and/or function in association with inflammatory activity.…”

Section: Discussionmentioning

confidence: 99%

Dynamic Changes in Brain Mesenchymal Perivascular Cells Associate with Multiple Sclerosis Disease Duration, Active Inflammation, and Demyelination

Iacobaeus¹,

Sugars²,

Andrén³

et al. 2017

Stem Cells Translational Medicine

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Vascular changes, including blood brain barrier destabilization, are common pathological features in multiple sclerosis (MS) lesions. Blood vessels within adult organs are reported to harbor mesenchymal stromal cells (MSCs) with phenotypical and functional characteristics similar to pericytes. We performed an immunohistochemical study of MSCs/pericytes in brain tissue from MS and healthy persons. Post-mortem brain tissue from patients with early progressive MS (EPMS), late stage progressive MS (LPMS), and healthy persons were analyzed for the MSC and pericyte markers CD146, platelet-derived growth factor receptor beta (PDGFRb), CD73, CD271, alphasmooth muscle actin, and Ki67. The MS samples included active, chronic active, chronic inactive lesions, and normal-appearing white matter. MSC and pericyte marker localization were detected in association with blood vessels, including subendothelial CD146 1 PDGFRb 1 Ki67 1 cells and CD73 1 CD271 1 PDGFRb 1 Ki67 -cells within the adventitia and perivascular areas. Both immunostained cell subpopulations were termed mesenchymal perivascular cells (MPCs). Quantitative analyses of immunostainings showed active lesions containing increased regions of CD146 1 PDGFRb 1 Ki67 1 and CD73 1 CD271 1 PDGFRb 1 Ki67 -MPC subpopulations compared to inactive lesions. Chronic lesions presented with decreased levels of CD146 1 PDGFRb 1 Ki67 1 MPC cells compared to control tissue. Furthermore, LPMS lesions displayed increased numbers of blood vessels harboring greatly enlarged CD73 1 CD271 1 adventitial and perivascular areas compared to control and EPMS tissue. In conclusion, we demonstrate the presence of MPC subgroups in control human brain vasculature, and their phenotypic changes in MS brain, which correlated with inflammation, demyelination and MS disease duration. Our findings demonstrate that brain-derived MPCs respond to pathologic mechanisms involved in MS disease progression and suggest that vessel-targeted therapeutics may benefit patients with progressive MS. STEM CELLS TRANSLATIONAL MEDICINE 2017;6:1840-1851 SIGNIFICANCE STATEMENTThis immunohistochemical study characterized vascular cells phenotypically similar to pericytes and mesenchymal stromal cells (MSCs) in brain tissue of multiple sclerosis (MS) and healthy persons. We found variations in phenotype, distribution, and proliferation of cells co-expressing markers for MSCs and pericytes that associated with inflammation and MS disease duration. Tissue from long standing MS presented with increased numbers of blood vessels that harbored expanded perivascular areas of cells staining positive for MSCs/pericyte markers. This is the first study to show involvement of MSC/pericyte phenotypic changes in MS pathology and highlights that vessel-targeted treatments may benefit late stage MS.

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“…Part 1 of the current special topic which was published in the preceding issue of Transfusion Medicine and Immunotherapy (issue 4, 2016) summarized the use of various stem cell populations such as mesenchymal as well as hematopoiesis- and adipose tissue-derived stem cells in the context of tissue regeneration, immune modulation and as transplantation additives [5,6,7]. In addition, several contributions provided comprehensive reviews on myocardial, cardiovascular and cardiovalvular tissue regeneration [8,9,10].…”

mentioning

confidence: 99%

Tissue Engineering and Regenerative Medicine - New Initiatives for Individual Treatment Offers

Frey

Zeisberger

Hoerstrup

2016

Transfus Med Hemother

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Mesenchymal Stem/Stromal Cells in Regenerative Medicine: Can Preconditioning Strategies Improve Therapeutic Efficacy

Cited by 107 publications

References 120 publications

Strategies to enhance paracrine potency of transplanted mesenchymal stem cells in intractable neonatal disorders

Strategies to enhance paracrine potency of transplanted mesenchymal stem cells in intractable neonatal disorders

Dynamic Changes in Brain Mesenchymal Perivascular Cells Associate with Multiple Sclerosis Disease Duration, Active Inflammation, and Demyelination

Tissue Engineering and Regenerative Medicine - New Initiatives for Individual Treatment Offers

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