Should hypoxia preconditioning become the standardized procedure for bone marrow MSCs preparation for clinical use?

Huang, Yong‐Can; Parolini, Ornella; Deng, Li; Yu, Bo

doi:10.1002/stem.2389

Cited by 19 publications

(12 citation statements)

References 19 publications

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“…Hypoxia preconditioning of MSCs significantly improves the therapeutic effects of MSCs. Furthermore, this procedure has been suggested for standardized protocols of MSC preparation for clinical applications [ 41 ]. The present work demonstrates that HIF-1 alpha overexpression confers to MSCs enhanced paracrine capacities which might participate in the previously described benefits of HIF-MSC therapy after myocardial infarction [ 7 ].…”

Section: Discussionmentioning

confidence: 99%

Overexpression of hypoxia-inducible factor 1 alpha improves immunomodulation by dental mesenchymal stem cells

et al. 2017

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BackgroundHuman dental mesenchymal stem cells (MSCs) are considered as highly accessible and attractive MSCs for use in regenerative medicine, yet some of their features are not as well characterized as other MSCs. Hypoxia-preconditioning and hypoxia-inducible factor 1 (HIF-1) alpha overexpression significantly improves MSC therapeutics, but the mechanisms involved are not fully understood. In the present study, we characterize immunomodulatory properties of dental MSCs and determine changes in their ability to modulate adaptive and innate immune populations after HIF-1 alpha overexpression.MethodsHuman dental MSCs were stably transduced with green fluorescent protein (GFP-MSCs) or GFP-HIF-1 alpha lentivirus vectors (HIF-MSCs). A hypoxic-like metabolic profile was confirmed by mitochondrial and glycolysis stress test. Capacity of HIF-MSCs to modulate T-cell activation, dendritic cell differentiation, monocyte migration, and polarizations towards macrophages and natural killer (NK) cell lytic activity was assessed by a number of functional assays in co-cultures. The expression of relevant factors were determined by polymerase chain reaction (PCR) analysis and enzyme-linked immunosorbent assay (ELISA).ResultsWhile HIF-1 alpha overexpression did not modify the inhibition of T-cell activation by MSCs, HIF-MSCs impaired dendritic cell differentiation more efficiently. In addition, HIF-MSCs showed a tendency to induce higher attraction of monocytes, which differentiate into suppressor macrophages, and exhibited enhanced resistance to NK cell-mediated lysis, which supports the improved therapeutic capacity of HIF-MSCs. HIF-MSCs also displayed a pro-angiogenic profile characterized by increased expression of CXCL12/SDF1 and CCL5/RANTES and complete loss of CXCL10/IP10 transcription.ConclusionsImmunomodulation and expression of trophic factors by dental MSCs make them perfect candidates for cell therapy. Overexpression of HIF-1 alpha enhances these features and increases their resistance to allogenic NK cell lysis and, hence, their potential in vivo lifespan. Our results further support the use of HIF-1 alpha-expressing dental MSCs for cell therapy in tissue injury and immune disorders.Electronic supplementary materialThe online version of this article (doi:10.1186/s13287-017-0659-2) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Overexpression of hypoxia-inducible factor 1 alpha improves immunomodulation by dental mesenchymal stem cells

et al. 2017

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“…Yet, some studies reported conflicting results showing negative or no effects on MSCs by hypoxia [ 34 – 36 ]. Thus, the question whether hypoxia preconditioning should become the standard of care for clinical application of MSCs remains to be answered [ 37 , 38 ]. Specifically, important questions that require further investigation are the precise oxygen concentration and appropriate incubation time that will provide the greatest benefit in terms of the therapeutic efficacy of MSCs.…”

Section: Introductionmentioning

confidence: 99%

Short-term physiological hypoxia potentiates the therapeutic function of mesenchymal stem cells

et al. 2018

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BackgroundIn the bone marrow, MSCs reside in a hypoxic milieu (1–5% O2) that is thought to preserve their multipotent state. Typically, in vitro expansion of MSCs is performed under normoxia (~ 21% O2), a process that has been shown to impair their function. Here, we evaluated the characteristics and function of MSCs cultured under hypoxia and hypothesized that, when compared to normoxia, dedicated hypoxia will augment the functional characteristics of MSCs.MethodsHuman and porcine bone marrow MSCs were obtained from fresh mononuclear cells. The first study evaluated MSC function following both long-term (10 days) and short-term (48 h) hypoxia (1% O2) culture. In our second study, we evaluated the functional characteristics of MSC cultured under short-term 2% and 5% hypoxia. MSCs were evaluated for their metabolic activity, proliferation, viability, clonogenicity, gene expression, and secretory capacity.ResultsIn long-term culture, common MSC surface marker expression (CD44 and CD105) dropped under hypoxia. Additionally, in long-term culture, MSCs proliferated significantly slower and provided lower yields under hypoxia. Conversely, in short-term culture, MSCs proliferated significantly faster under hypoxia. In both long-term and short-term cultures, MSC metabolic activity was significantly higher under hypoxia. Furthermore, MSCs cultured under hypoxia had upregulated expression of VEGF with concomitant downregulation of HMGB1 and the apoptotic genes BCL-2 and CASP3. Finally, in both hypoxia cultures, the pro-inflammatory cytokine, IL-8, was suppressed, while levels of the anti-inflammatories, IL-1ra and GM-CSF, were elevated in short-term hypoxia only.ConclusionsIn this study, we demonstrate that hypoxia augments the therapeutic characteristics of both porcine and human MSCs. Yet, short-term 2% hypoxia offers the greatest benefit overall, exemplified by the increase in proliferation, self-renewing capacity, and modulation of key genes and the inflammatory milieu as compared to normoxia. These data are important for generating robust MSCs with augmented function for clinical applications.

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“…Although oxygen concentration varies depending on the tissue type, in several tissues or organs, such as bone marrow (1–6%), adipose tissue (2–8%), brain (0.5–8%), heart (4–14%), liver (4–14%), and circulation (4–14%), they are remarkably lower than normoxia (21% O 2 ) [19]. Accumulating evidence suggests that hypoxic preconditioning enhances plasticity, survival, proliferation, engraftment, and genetic stability of MSCs [4,7,19]. However, optimum oxygen tension, suitable culture time, paracrine action, and the underlying mechanism need further investigation.…”

Section: Discussionmentioning

confidence: 99%

“…Conversely, in preclinical and clinical applications, MSC-based therapeutics are delivered at ischemic and hypoxic injured sites. Therefore, it has been suggested that optimization of hypoxic preconditioning for MSC expansion is important for clinical development of MSC-based therapies [4]. Accumulating evidence has shown that hypoxic preconditioning of MSCs promotes cell survival, proliferation, motility, metabolic changes, and cell retention in vitro and in vivo [5,6,7,8].…”

Section: Introductionmentioning

confidence: 99%

Hypoxic Preconditioning Promotes the Bioactivities of Mesenchymal Stem Cells via the HIF-1α-GRP78-Akt Axis

Lee

Yoon

Lee

2017

IJMS

114

104

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Mesenchymal stem cells (MSC) are ideal materials for stem cell-based therapy. As MSCs reside in hypoxic microenvironments (low oxygen tension of 1% to 7%), several studies have focused on the beneficial effects of hypoxic preconditioning on MSC survival; however, the mechanisms underlying such effects remain unclear. This study aimed to uncover the potential mechanism involving 78-kDa glucose-regulated protein (GRP78) to explain the enhanced MSC bioactivity and survival in hindlimb ischemia. Under hypoxia (2% O2), the expression of GRP78 was significantly increased via hypoxia-inducible factor (HIF)-1α. Hypoxia-induced GRP78 promoted the proliferation and migration potential of MSCs through the HIF-1α-GRP78-Akt signal axis. In a murine hind-limb ischemia model, hypoxic preconditioning enhanced the survival and proliferation of transplanted MSCs through suppression of the cell death signal pathway and augmentation of angiogenic cytokine secretion. These effects were regulated by GRP78. Our findings indicate that hypoxic preconditioning promotes survival, proliferation, and angiogenic cytokine secretion of MSCs via the HIF-1α-GRP78-Akt signal pathway, suggesting that hypoxia-preconditioned MSCs might provide a therapeutic strategy for MSC-based therapies and that GRP78 represents a potential target for the development of functional MSCs.

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Should hypoxia preconditioning become the standardized procedure for bone marrow MSCs preparation for clinical use?

Cited by 19 publications

References 19 publications

Overexpression of hypoxia-inducible factor 1 alpha improves immunomodulation by dental mesenchymal stem cells

Overexpression of hypoxia-inducible factor 1 alpha improves immunomodulation by dental mesenchymal stem cells

Short-term physiological hypoxia potentiates the therapeutic function of mesenchymal stem cells

Hypoxic Preconditioning Promotes the Bioactivities of Mesenchymal Stem Cells via the HIF-1α-GRP78-Akt Axis

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