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Stem cell research has expanded at an exponential rate, but its therapeutic applications have progressed much more slowly. Currently, the research focuses on understanding embryonic, adult, and inducible pluripotent stem cells. Translation of adult stem cell research has established a definitive benefit that is greater than that of the current standard of care in the field of cardiovascular medicine. The future of stem cell research and therapy will continue to provide novel avenues of diagnostics, therapeutics, and tissue regeneration. Here we discuss a brief history of stem cell research as it transitioned from the 20th to the 21st century. We address lessons learned in the first decade of the new millennium that could help guide others to translate research into therapy across disciplines. Finally, we highlight future goals and challenges that must be overcome and offer some perspective on the bright future of stem cell research and therapy. [ABSTRACT FROM AUTHOR]

Background: Radiotherapy is widely used and effective for treating brain tumours, but inevitably impairs cognition as it arrests cellular processes important for learning and memory. This is particularly evident in the aged brain with limited regenerative capacity, where radiation produces irreparable neuronal damage and activation of neighbouring microglia. The latter is responsible for increased neuronal death and contributes to cognitive decline after treatment. To date, there are few effective means to prevent cognitive deficits after radiotherapy.Methods: Here we implanted hematopoietic stem cells (HSCs) from young or old (2- or 18-month-old, respectively) donor mice expressing green fluorescent protein (GFP) into old recipients and assessed cognitive abilities 3 months post-reconstitution.Results: Regardless of donor age, GFP+ cells homed to the brain of old recipients and expressed the macrophage/microglial marker, Iba1. However, only young cells attenuated deficits in novel object recognition and spatial memory and learning in old mice post-irradiation. Mechanistically, old recipients that received young HSCs, but not old, displayed significantly greater dendritic spine density and long-term potentiation (LTP) in CA1 neurons of the hippocampus. Lastly, we found that GFP+/Iba1+ cells from young and old donors were differentially polarized to an anti- and pro-inflammatory phenotype and produced neuroprotective factors and reactive nitrogen species in vivo, respectively.Conclusion: Our results suggest aged peripherally derived microglia-like cells may exacerbate cognitive impairments after radiotherapy, whereas young microglia-like cells are polarized to a reparative phenotype in the irradiated brain, particularly in neural circuits associated with rewards, learning, and memory. These findings present a proof-of-principle for effectively reinstating central cognitive function of irradiated brains with peripheral stem cells from young donor bone marrow. [ABSTRACT FROM AUTHOR]

Recruitment of stem cells from the bone marrow (BM) is an important aspect of cardiac healing that becomes inefficient with age. We investigated the role of young stem cell antigen 1 (Sca-1)-positive BM cells on the aged heart by microarray analysis after BM reconstitution. Sca-1+ and Sca-1- BM cells from young green fluorescent protein (GFP)-positive mice were used to reconstitute the BM of aged mice. Myocardial infarction (MI) was induced 3 mo later. GFP+ cells were more abundant in the BM, blood, and heart of Sca-1+ mice, which corresponded to preserved cardiac function after MI. At baseline, Sca-1+ BM reconstitution increased cardiac expression of serum response factor, vascular endothelial growth factor A, and myogenic genes, but reduced the expression of Il-1β. After MI, inflammation was identified as a key difference between Sca-1- and Sca-1+ groups, as cytokine expression and cell surface markers associated with inflammatory cells were up-regulated with Sca-1+ reconstitution. Mac-3 and F4/80 staining showed that the postinfarction heart was composed of a mixture of GFP+ (donor) macrophages, GFP- (host) macrophages, and GFP+ cells that did not contribute to the macrophage population. This study demonstrates that Sca-1+ BM cells regulate cardiac healing though an acute inflammatory response and also before injury by stimulating formation of a beneficial cardiac niche. [ABSTRACT FROM AUTHOR]

Background--Allogeneic mesenchymal stem cells (MSCs) were immunoprivileged early after cardiac implantation and improved heart function in preclinical and clinical studies. However, long-term preclinical studies demonstrated that allogeneic MSCs lost their immunoprivilege and were rejected in the injured myocardium, resulting in recurrent ventricular dysfunction. This study identifies some of the mechanisms responsible for the immune switch in MSCs and suggests a new treatment to maintain immunoprivilege and preserve heart function. Methods and Results--Rat MSC immunoprivilege was mediated by prostaglandin E2 (PGE2)-induced secretion of 2 critical chemokines, CCL12 and CCL5. These chemokines stimulated the chemoattraction of T cells toward MSCs, suppressed cytotoxic T-cell proliferation, and induced the production of T regulatory cells. MSCs treated with 5-azacytidine for 24 hours differentiated into myogenic cells after 2 weeks, which was associated with decreased PGE2 and chemokine production and the loss of immunoprivilege. Treatment of differentiated MSCs with PGE2 restored chemokine levels and preserved MSC immunoprivilege. In a rat myocardial infarction model, allogeneic MSCs (3x106 cells/rat) were injected into the infarct region with or without a biodegradable hydrogel that slowly released PGE2. Five weeks later, the transplanted MSCs expressed myogenic lineage markers and were rejected in the control group, but in the PGE2-treated group, the transplanted cells survived and heart function improved. Conclusions--Allogeneic MSCs maintained immunoprivilege by PGE2-induced secretion of chemokines CCL12 and CCL5. Differentiation of MSCs decreased PGE2 levels, and immunoprivilege was lost. Maintaining PGE2 levels preserved immunoprivilege after differentiation, prevented rejection of implanted MSCs, and restored cardiac function. [ABSTRACT FROM AUTHOR]

Cardiac cell therapies offer distinct and exciting advantages over current treatments to prevent postinfarction heart failure because they can reverse ventricular remodeling and improve function, but only if the implanted stem cells contribute biological functions and achieve prolonged engraftment within the hostile environment of the damaged heart. Unfortunately, function is diminished in autologous stem cells isolated from older patients and those with comorbidities, and so clinical trials testing the implantation of healthy, allogeneic bone marrow–derived stromal cells (MSCs) isolated from young donors are currently underway. MSCs are unique because, in addition to exerting paracrine effects that restore blood flow and recruit endogenous stem cells to the infarct, they exhibit immune-modulating properties in culture that—if retained after allogeneic implantation—imply the cells may escape immune recognition within the heart. At present, the scope of MSC immune modulation after implantation is unclear. (J Card Surg 2010;25:359-366) [ABSTRACT FROM AUTHOR]

Cardiovascular disease is the numberone cause of mortality in the developed world. The aim of this study is to define the mechanisms by which bone marrow progenitor cells are mobilized in response to cardiac ischemic injury. We used a closed-chest model of murine cardiac infarction/reperfusion, which segregated the surgical thoracotomy from the induction of cardiac infarction, so that we could study isolated fluctuations in cytokines without the confounding impact of surgery. We show here that bone marrow activation of the c-kit tyrosine kinase receptor in response to released soluble KitL is necessary for bone marrow progenitor cell mobilization after ischemic cardiac injury. We also show that release of KitL and c-kit activation require the activity of matrix metallo-proteinase-9 within the bone marrow compartment. Finally, we demonstrate that mice with c-kit dysfunction develop cardiac failure after myocardial infarction and that bone marrow transplantation rescues the failing cardiac phenotype. In light of the ongoing trials of progenitor cell therapy for heart disease, our study outlines the endogenous repair mechanisms that are invoked after cardiac injury. Amplification of this pathway may aid in restoration of cardiac function after myocardial infarction. [ABSTRACT FROM AUTHOR]

Reduced quantity and quality of stem cells in aged individuals hinders cardiac repair and regeneration after injury. We used young bone marrow (BM) stem cell antigen 1 (Sca‐1) cells to reconstitute aged BM and rejuvenate the aged heart, and examined the underlying molecular mechanisms. BM Sca‐1+ or Sca‐1− cells from young (2–3 months) or aged (18–19 months) GFP transgenic mice were transplanted into lethally irradiated aged mice to generate 4 groups of chimeras: young Sca‐1+, young Sca‐1−, old Sca‐1+, and old Sca‐1−. Four months later, expression of rejuvenation‐related genes (Bmi1, Cbx8, PNUTS, Sirt1, Sirt2, Sirt6) and proteins (CDK2, CDK4) was increased along with telomerase activity and telomerase‐related protein (DNA‐PKcs, TRF‐2) expression, whereas expression of senescence‐related genes (p16INK4a, P19ARF, p27Kip1) and proteins (p16INK4a, p27Kip1) was decreased in Sca‐1+ chimeric hearts, especially in the young group. Host cardiac endothelial cells (GFP−CD31+) but not cardiomyocytes were the primary cell type rejuvenated by young Sca‐1+ cells as shown by improved proliferation, migration, and tubular formation abilities. C‐X‐C chemokine CXCL12 was the factor most highly expressed in homed donor BM (GFP+) cells isolated from young Sca‐1+ chimeric hearts. Protein expression of Cxcr4, phospho‐Akt, and phospho‐FoxO3a in endothelial cells derived from the aged chimeric heart was increased, especially in the young Sca‐1+ group. Reconstitution of aged BM with young Sca‐1+ cells resulted in effective homing of functional stem cells in the aged heart. These young, regenerative stem cells promoted aged heart rejuvenation through activation of the Cxcl12/Cxcr4 pathway of cardiac endothelial cells. [ABSTRACT FROM AUTHOR]

Introduction: Cardiovascular disease is the leading cause of death worldwide and its prevalence increases with age. Replacing the bone marrow (BM) stem cells of aged mice with young BM stem cell antigen-1+ (Y-Sca-1+) cells rejuvenates the response of the aged heart to injury. Autophagy, a critical cellular recycling process, decreases with age. We hypothesized that the high rate of autophagy in Y-Sca-1+ BM cells contributes to the rejuvenation of the aged heart and improves tissue repair. Methods: In vitro: Young (Y) and old (O) Sca-1+ BM cells were isolated from Y and O mice and cultured in normoxia and hypoxia conditions to examine the rate of autophagy. To determine the effect of secretory factors, conditioned medium (CM) was produced from Y-Sca-1+ and O-Sca-1+ cells and used to culture old primary cardiac fibroblasts (O-Fs). In vivo: Old mice were lethally irradiated and reconstituted with Y-Sca-1+ or O-Sca-1+ BM cells from GFP mice to generate YP and OP chimeras, respectively. After 3 months, mice were sacrificed and hearts collected for molecular and histological analyses. Results: In vitro: Cultured Y-Sca-1+ cells exhibited a higher rate of autophagy and were more responsive to hypoxia-induced autophagy than O-Sca-1+ cells. Thus, Y-Sca-1+ cells may pre-condition and rejuvenate the aged heat. In support of this theory, factors secreted from Y-Sca-1+, but not O-Sca-1+ BM cells, enhanced several functions of O-Fs, including autophagy, cell migration, proliferation and trans-differentiation. This phenotype was not observed after boiling the CM, suggesting that rejuvenation is mediated by a secreted factor. In vivo: We found that reconstitution of aged mice with Y-Sca-1+ BM cells improved autophagy of the aged heart. The autophagy rate was increased in YP relative to OP hearts as demonstrated by an increase in the LC3b II/I ratio. Immunostaining of the reconstituted heart showed that the number of LC3b+ cells was 3-fold higher in YP than OP hearts. These LC3b+ cells were both donor and recepiant cells. Conclusions: The increase in autophagy rate in the YP heart suggests that autophagy is one of the mechanisms involved in rejuvenation of the aged heart after BM reconstitution. Y-Sca-1+ BM cells secret factors that improve the autophagy of recepient cardiac cells. [ABSTRACT FROM AUTHOR]

Introduction: Clinical trials of cell therapy for post-injury conditioning of the myocardium have shown only modest improvements, perhaps because the majority of donor cells die in the harsh post-ischemic environment. Hypothesis: We hypothesize that pre-conditioning the myocardium by delivering human CD34+ (hCD34+) cells through bone marrow (BM) engraftment may prevent adverse remodeling and heart failure post myocardial infarct (MI). BM engraftment may be especially important in elderly patients because of their reduced stem cell function. Methods: BM aspirates from 40 patients undergoing open-heart surgery were collected. Mononuclear cells were isolated and stem cell subpopulations were quantified using flow cytometry and magnetically sorted. Function of hCD34+ cells was analyzed by the colony forming unit (CFU) assay and their ability to reconstitute irradiated immune-deficient NSG mice. Engraftment was quantified as hCD45 chimerism by flow cytometry. To evaluate the benefits of hCD34+ cells in cardiac repair, coronary artery ligation was performed 12 weeks post-reconstitution. Left ventricular (LV) function and histology were assessed by echocardiography and immunohistochemistry. Results: Older patients (>60 years old, n=24) had lower numbers (p=0.0008) and reduced function (p<0.0001) of hCD34+ cells. We found a significant difference in the homing ability of hCD34+ (n=7) vs. hCD34- (n=6) cells to the bone marrow, blood, spleen and heart (p<0.05, all groups) 12 weeks post-reconstitution. hCD34+ mice engrafted with young patients' cells had higher reconstitution in blood, spleen and heart (p<0.01, all groups). At 4 weeks post-ligation, hCD34+ mice (n=8) had improved LV function, with greater fractional shortening (p=0.003), reduced LV dilation (p=0.02) and reduced scar size (p=0.0002). Immunohistochemistry of the peri-infarct region of CD34+ mice showed increased hCD34-derived vessels, indicating their role in infarct healing. Conclusions: hCD34+ cells have reduced frequency and function in older patients, but engraft and protect the myocardium from functional decline post-MI. Cardiac pre-conditioning by restoration of aged hCD34+ cells is a promising avenue for preventing cardiac dysfunction post-MI. [ABSTRACT FROM AUTHOR]