**3.2. Vascular disease**

culture-expanded in vitro and stimulated with vascular endothelial growth factor-A (VEGF-A) (165) the week before treatment. The six month follow-up results demonstrated safety, and although a significant increase in exercise capacity was observed in the patients treated with the MSCs but not with placebo, there was no statistically significant difference between the MSC

An important issue in this new field is whether MSCs can be used as an allograft [5, 7, 89], avoiding the need for bone marrow aspiration of patients and tissue culture delays prior to treatment. Furthermore, the function of autologous MSCs may be impaired in patients with comorbidities and/or advanced age [101–104]. A meta-analysis of 82 preclinical studies [144] demonstrated that allogeneic therapy is safe and at least as effective as autologous MSC therapy, suggesting

The therapeutic benefit of allogeneic MSCs versus placebo delivered intravenously has been investigated in patients after acute MI [11, 145, 146]. Not only did these results show the safety of allogeneic MSC delivery to humans, but also moreover, echocardiography demonstrated a 6% increase in ejection fraction at 3 months for patients treated with MSCs. Moreover, the percutaneous stem cell injection delivery effects on neo-myogenesis (POSEIDON) trial compared allogeneic vs. autologous MSCs delivered by transendocardial stem cell injection in patients with chronic ischemic cardiomyopathy and showed that both MSC types are safe and clinically effective [7, 147]. Similarly, the percutaneous stem cell injection delivery effects on neo-myogenesis – dilated cardiomyopathy (POSEIDON-DCM) trial demonstrated safety and efficacy of transendocardial autologous vs. allogeneic MSC therapy in patients with nonischemic, dilated cardiomyopathy, with a cardiac function efficacy preference toward alloge-

that allogeneic MSCs are characteristically immunomodulatory, as discussed above.

and placebo treatment groups.

**Figure 6.** Effects Of mesenchymal stem cell therapy in heart disease.

154 Stromal Cells - Structure, Function, and Therapeutic Implications

neic MSCs [5].

Endothelial dysfunction is characterized by impaired endothelial vasodilation, a proinflammatory and prothrombotic state, and impaired bioactivity of EPCs and contributes to the pathophysiology of most forms of cardiovascular disease, including hypertension, coronary artery disease, heart failure, peripheral vascular disease, kidney disease, diabetes mellitus, and metabolic syndrome [156, 157]. Endothelial function is implicated in heart failure [158] and we have studied the therapeutic potential of MSCs in restoring endothelial function in patients with ischemic and non-ischemic cardiomyopathy [81]. As mentioned above, individuals with heart failure received either autologous or allogeneic MSCs, and those in the allogeneic MSC group exhibit increased EPC colony formation and improved flow-mediated vasodilation (FMD), both of which strongly correlate with improved endothelial function [158, 159] (**Figure 7**). Moreover, patients who received allogeneic MSCs had reduced levels of VEGF. Elevated VEGF is associated with heart failure progression [160]. The concordant restitution of these parameters to near normal after allogeneic MSC therapy has significant clinical implications for the heart failure population and may play a critical role in the advancement of cardiovascular treatment modalities.

It is well established that cardiovascular disease is the leading cause of death and disability among people with type 2 diabetes mellitus [161] and has long been appreciated that endothelial dysfunction underlies the high rates of cardiovascular disease associated with long-term diabetes [162]. The persistent hyperglycemia and other metabolic abnormalities directly affect the endothelium, contributing to the pathophysiology of disease [163]. Based on our findings of improved endothelial function after allogeneic MSC treatment in patients with heart failure [81], we are conducting a clinical trial entitled, Allogeneic Mesenchymal Human Stem Cells Infusion Therapy for Endothelial Dysfunction in Diabetic Subjects (ACESO; NCT02886884) to investigate whether intravenously delivered MSCs restore endothelial function parameters, including FMD and EPC function, as well as decrease circulating inflammatory markers and improve clinical parameters of diabetes. Similarly, the Intravenous Infusion of Umbilical Cord Tissue (UC) Derived Mesenchymal Stem Cells (MSCs) Versus Bone Marrow (BM) Derived MSCs to Evaluate Cytokine Suppression in Patients With Chronic Inflammation Due to Metabolic Syndrome (CERES; NCT03059355) trial is testing MSC therapies to restore endo-

Mesenchymal Stromal Cells as a Therapeutic Intervention

http://dx.doi.org/10.5772/intechopen.78586

157

Peripheral artery disease is generally caused by atherosclerosis in which cholesterol plaque builds up, ultimately weakening blood vessel walls and restricting blood flow, severely impairing endothelial function. The evaluation of cell therapy on exercise performance and limb perfusion in peripheral artery disease: The CCTRN patients with intermittent claudication injected with ALDH bright cells (PACE) Trial demonstrated safety but no improvement in peak walking time or capillary perfusion [164]. In patients with complete occlusion of femoral arteries, a post-hoc exploratory analysis suggested an improvement in the number of collateral arteries. Future clinical trials testing different cell types, doses, and administration

routes are needed to optimize peripheral artery disease treatment.

**4. MSCs as immunomodulatory, anti-Inflammatory, anti-fibrotic,** 

MSCs exhibit immune-privileged properties in vitro and in vivo [165] likely due to the absence of MHC II, B-7 costimulatory molecule, and CD40 ligand [90–92, 166] (**Figure 8**). The lack of costimulatory molecules prevents T-cell responses and also induces an immunosuppressive local microenvironment through the production of prostaglandins and other soluble mediators including nitric oxide, indoleamine 2,3-dioxygenase, and heme oxygenase-1 [92, 167–170]. MSCs reduce the respiratory burst that follows neutrophilic responses by releasing interleukin (IL)-6 [171]. They also inhibit the differentiation of immature monocytes into dendritic cells hence the antigen presentation to naïve T cells is greatly impaired [172]. In addition, MSCs release soluble factors, such as hepatocyte growth factor and transforming growth factor (TGF)-β1 [173], that suppress the proliferation of cytotoxic and helper T-(Th) cells. MSCs also stimulate Foxp3+ regulatory T cells with concurrent suppression of Th1, Th2, or Th17 responses [174]. These findings suggest that MSCs are an effective therapeutic strategy to induce tolerance in solid organ trans-

thelial function.

**and anti-rejection therapy**

plantation [175].

**Figure 7.** MSCs in vascular disease. Allogeneic mesenchymal stem cell therapy can help restore endothelial function in patients with cardiomyopathy by increasing EPC CFUs (A) and improving FMD (E) when compared to autologous therapy (B and F). Representative EPC-CFUs plated on fibronectin for 5 days before (C) and after (D) allogeneic MSC administration (magnification 20x). *Reproduced from Premer C et al., EBioMed, 2015.*

It is well established that cardiovascular disease is the leading cause of death and disability among people with type 2 diabetes mellitus [161] and has long been appreciated that endothelial dysfunction underlies the high rates of cardiovascular disease associated with long-term diabetes [162]. The persistent hyperglycemia and other metabolic abnormalities directly affect the endothelium, contributing to the pathophysiology of disease [163]. Based on our findings of improved endothelial function after allogeneic MSC treatment in patients with heart failure [81], we are conducting a clinical trial entitled, Allogeneic Mesenchymal Human Stem Cells Infusion Therapy for Endothelial Dysfunction in Diabetic Subjects (ACESO; NCT02886884) to investigate whether intravenously delivered MSCs restore endothelial function parameters, including FMD and EPC function, as well as decrease circulating inflammatory markers and improve clinical parameters of diabetes. Similarly, the Intravenous Infusion of Umbilical Cord Tissue (UC) Derived Mesenchymal Stem Cells (MSCs) Versus Bone Marrow (BM) Derived MSCs to Evaluate Cytokine Suppression in Patients With Chronic Inflammation Due to Metabolic Syndrome (CERES; NCT03059355) trial is testing MSC therapies to restore endothelial function.

pathophysiology of most forms of cardiovascular disease, including hypertension, coronary artery disease, heart failure, peripheral vascular disease, kidney disease, diabetes mellitus, and metabolic syndrome [156, 157]. Endothelial function is implicated in heart failure [158] and we have studied the therapeutic potential of MSCs in restoring endothelial function in patients with ischemic and non-ischemic cardiomyopathy [81]. As mentioned above, individuals with heart failure received either autologous or allogeneic MSCs, and those in the allogeneic MSC group exhibit increased EPC colony formation and improved flow-mediated vasodilation (FMD), both of which strongly correlate with improved endothelial function [158, 159] (**Figure 7**). Moreover, patients who received allogeneic MSCs had reduced levels of VEGF. Elevated VEGF is associated with heart failure progression [160]. The concordant restitution of these parameters to near normal after allogeneic MSC therapy has significant clinical implications for the heart failure population and may play a critical role in the advancement

**Figure 7.** MSCs in vascular disease. Allogeneic mesenchymal stem cell therapy can help restore endothelial function in patients with cardiomyopathy by increasing EPC CFUs (A) and improving FMD (E) when compared to autologous therapy (B and F). Representative EPC-CFUs plated on fibronectin for 5 days before (C) and after (D) allogeneic MSC

administration (magnification 20x). *Reproduced from Premer C et al., EBioMed, 2015.*

of cardiovascular treatment modalities.

156 Stromal Cells - Structure, Function, and Therapeutic Implications

Peripheral artery disease is generally caused by atherosclerosis in which cholesterol plaque builds up, ultimately weakening blood vessel walls and restricting blood flow, severely impairing endothelial function. The evaluation of cell therapy on exercise performance and limb perfusion in peripheral artery disease: The CCTRN patients with intermittent claudication injected with ALDH bright cells (PACE) Trial demonstrated safety but no improvement in peak walking time or capillary perfusion [164]. In patients with complete occlusion of femoral arteries, a post-hoc exploratory analysis suggested an improvement in the number of collateral arteries. Future clinical trials testing different cell types, doses, and administration routes are needed to optimize peripheral artery disease treatment.
