Rationale: Mesenchymal stromal cell–based therapy is promising against ischemic heart failure. However, its efficacy is limited due to low cell retention and poor paracrine function. A transmembran...

N-Cadherin Overexpression Mobilizes the Protective Effects of Mesenchymal Stromal Cells Against Ischemic Heart Injury Through a β-Catenin–Dependent Manner

Precision medicine in distinct heart failure phenotypes: Focus on clinical epigenetics.

Diabetes mellitus increases the risk and accelerates the course of peripheral artery disease, making patients more susceptible to ischemic events and infections and delaying tissue healing. Current understanding of pathogenic mechanisms is mainly based on the negative influence of diabetes mellitus on atherosclerotic disease and inflammation. In recent years, the novel concept that diabetes mellitus can impinge on endogenous regenerative processes has been introduced. Diabetes mellitus affects regeneration at the local level, disturbing proper angiogenesis, collateral artery formation, and muscle repair. Recent evidence indicates that an impairment in vascular mural cells, alias pericytes, may participate in diabetic peripheral vasculopathy. Moreover, the bone marrow undergoes a global remodeling, consisting of microvessels and sensory neurons rarefaction and fat accumulation, which creates a hostile microenvironment for resident stem cells. Bone marrow remodeling is also responsible for detrimental systemic effects. In particular, the aid of reparative cells from the bone marrow is compromised: these elements are released in an improper manner and become harmful vectors of inflammatory and antiangiogenic molecules and noncoding RNAs. This new understanding of impaired regeneration is inspiring new therapeutic options for the treatment of ischemic complications in people with diabetes mellitus.

Impaired Regeneration Contributes to Poor Outcomes in Diabetic Peripheral Artery Disease

Sensory neuropathy is common in people with diabetes; neuropathy can also affect the bone marrow of individuals with type 2 diabetes. However, no information exists on the state of bone marrow sensory innervation in type 1 diabetes. Sensory neurons are trophically dependent on nerve growth factor (NGF) for their survival. The aim of this investigation was twofold: (1) to determine if sensory neuropathy affects the bone marrow in a mouse model of type 1 diabetes, with consequences for stem cell liberation after tissue injury; and (2) to verify if a single systemic injection of the NGF gene exerts long-term beneficial effects on these phenomena. A mouse model of type 1 diabetes was generated in CD1 mice by administration of streptozotocin; vehicle was administered to non-diabetic control animals. Diabetic animals were randomised to receive systemic gene therapy with either human NGF or β-galactosidase. After 13 weeks, limb ischaemia was induced in both groups to study the recovery post injury. When the animals were killed, samples of tissue and peripheral blood were taken to assess stem cell mobilisation and homing, levels of substance P and muscle vascularisation. An in vitro cellular model was adopted to verify signalling downstream to human NGF and related neurotrophic or pro-apoptotic effects. Normally distributed variables were compared between groups using the unpaired Student’s t test and non-normally distributed variables were assessed by the Wilcoxon–Mann–Whitney test. The Fisher’s exact test was employed for categorical variables. Immunohistochemistry indicated a 3.3-fold reduction in the number of substance P-positive nociceptive fibres in the bone marrow of type 1 diabetic mice (p < 0.001 vs non-diabetic). Moreover, diabetes abrogated the creation of a neurokinin gradient which, in non-diabetic mice, favoured the mobilisation and homing of bone-marrow-derived stem cells expressing the substance P receptor neurokinin 1 receptor (NK1R). Pre-emptive gene therapy with NGF prevented bone marrow denervation, contrasting with the inhibitory effect of diabetes on the mobilisation of NK1R-expressing stem cells, and restored blood flow recovery from limb ischaemia. In vitro hNGF induced neurite outgrowth and exerted anti-apoptotic actions on rat PC12 cells exposed to high glucose via activation of the canonical neurotrophic tyrosine kinase receptor type 1 (TrkA) signalling pathway. This study shows, for the first time, the occurrence of sensory neuropathy in the bone marrow of type 1 diabetic mice, which translates into an altered modulation of substance P and depressed release of substance P-responsive stem cells following ischaemia. NGF therapy improves bone marrow sensory innervation, with benefits for healing on the occurrence of peripheral ischaemia. Nociceptors may represent a new target for the treatment of ischaemic complications in diabetes.

/pdf/nerve-growth-factor-gene-therapy-improves-bone-marrow-5c232zy6ea.pdf

Nerve growth factor gene therapy improves bone marrow sensory innervation and nociceptor-mediated stem cell release in a mouse model of type 1 diabetes with limb ischaemia.

Stem cells represent an attractive resource for cardiac regeneration. However, the survival and function of transplanted stem cells is poor and remains a major challenge for the development of effective therapies. As two main cell types currently under investigation in heart repair, mesenchymal stromal cells (MSCs) indirectly support endogenous regenerative capacities after transplantation, while induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) functionally integrate into the damaged myocardium and directly contribute to the restoration of its pump function. These two cell types are exposed to a common microenvironment with many stressors in ischemic heart tissue. This review summarizes the research progress on the mechanisms and challenges of MSCs and iPSC-CMs in post-MI heart repair, introduces several randomized clinical trials with 3D-mapping-guided cell therapy, and outlines recent findings related to the factors that affect the survival and function of stem cells. We also discuss the future directions for optimization such as biomaterial utilization, cell combinations, and intravenous injection of engineered nucleus-free MSCs. 

Stem cell-based therapy in cardiac repair after myocardial infarction: Promise, challenges, and future directions.

https://air.uniud.it/bitstream/11390/1071130/1/mt2015167a-3.pdf

Cardiac Nerve Growth Factor Overexpression Induces Bone Marrow-derived Progenitor Cells Mobilization and Homing to the Infarcted Heart.

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Cardiac Nerve Growth Factor Overexpression Induces Bone Marrow-derived Progenitor Cells Mobilization and Homing to the Infarcted Heart.