Reconstitution of aged bone marrow with young cells repopulates cardiac-resident bone marrow-derived progenitor cells and prevents cardiac dysfunction after a myocardial infarction
Abstract:Bone marrow reconstitution with young BM cells in aged recipients restored progenitors in both the BM and, most importantly, the myocardium. The number and function of cardiac-resident BM-derived progenitor cells in the aged myocardium prior to injury was the major determinant for successful recovery of cardiac function. The aged heart was rejuvenated with young BM cells.
“…This data allows us to hypothesize that the bone marrow SSEA1+ cells may replenish the activated myocardial SSEA1 population. Previous reports have described the phenomenon of bone marrow cells contributing to the cardiac progenitor pool in the myocardium [7,36]. This is the first evidence that suggests a similar occurrence with SSEA1+ cells.…”
RationaleStage specific embryonic antigen 1+ (SSEA1+) cells have been described as the most primitive mesenchymal progenitor cell in the bone marrow. Cardiac injury mobilizes SSEA1+ cells into the peripheral blood but their in vivo function has not been characterized.ObjectiveWe generated animals with chimeric bone marrow to determine the fate and function of bone marrow SSEA1+ cells in response to acute cardiac pressure overload.Methods and ResultsLethally irradiated mice were transplanted with normal bone marrow where the wild-type SSEA1+ cells were replaced with green fluorescent protein (GFP) SSEA1+ cells. Cardiac injury was induced by trans-aortic constriction (TAC). We identified significant GFP+ cell engraftment into the myocardium after TAC. Bone marrow GFP+ SSEA1 derived cells acquired markers of endothelial lineage, but did not express markers of c-kit+ cardiac progenitor cells. The function of bone marrow SSEA1+ cells after TAC was determined by transplanting lethally irradiated mice with bone marrow depleted of SSEA1+ cells (SSEA1-BM). The cardiac function of SSEA1-BM mice declined at a greater rate after TAC compared to their complete bone marrow transplant counterparts and was associated with decreased bone marrow cell engraftment and greater vessel rarefication in the myocardium.ConclusionsThese results provide evidence for the recruitment of endogenous bone marrow SSEA1+ cells to the myocardium after TAC. We demonstrate that, in vivo, bone marrow SSEA1+ cells have the differentiation potential to acquire endothelial lineage markers. We also show that bone marrow SSEA1+ deficiency is associated with a reduced compensatory capacity to cardiac pressure overload, suggesting their importance in cardiac homeostasis. These data demonstrate that bone marrow SSEA1+ cells are critical for sustaining vascular density and cardiac repair to pressure overload.
“…This data allows us to hypothesize that the bone marrow SSEA1+ cells may replenish the activated myocardial SSEA1 population. Previous reports have described the phenomenon of bone marrow cells contributing to the cardiac progenitor pool in the myocardium [7,36]. This is the first evidence that suggests a similar occurrence with SSEA1+ cells.…”
RationaleStage specific embryonic antigen 1+ (SSEA1+) cells have been described as the most primitive mesenchymal progenitor cell in the bone marrow. Cardiac injury mobilizes SSEA1+ cells into the peripheral blood but their in vivo function has not been characterized.ObjectiveWe generated animals with chimeric bone marrow to determine the fate and function of bone marrow SSEA1+ cells in response to acute cardiac pressure overload.Methods and ResultsLethally irradiated mice were transplanted with normal bone marrow where the wild-type SSEA1+ cells were replaced with green fluorescent protein (GFP) SSEA1+ cells. Cardiac injury was induced by trans-aortic constriction (TAC). We identified significant GFP+ cell engraftment into the myocardium after TAC. Bone marrow GFP+ SSEA1 derived cells acquired markers of endothelial lineage, but did not express markers of c-kit+ cardiac progenitor cells. The function of bone marrow SSEA1+ cells after TAC was determined by transplanting lethally irradiated mice with bone marrow depleted of SSEA1+ cells (SSEA1-BM). The cardiac function of SSEA1-BM mice declined at a greater rate after TAC compared to their complete bone marrow transplant counterparts and was associated with decreased bone marrow cell engraftment and greater vessel rarefication in the myocardium.ConclusionsThese results provide evidence for the recruitment of endogenous bone marrow SSEA1+ cells to the myocardium after TAC. We demonstrate that, in vivo, bone marrow SSEA1+ cells have the differentiation potential to acquire endothelial lineage markers. We also show that bone marrow SSEA1+ deficiency is associated with a reduced compensatory capacity to cardiac pressure overload, suggesting their importance in cardiac homeostasis. These data demonstrate that bone marrow SSEA1+ cells are critical for sustaining vascular density and cardiac repair to pressure overload.
“…Old donors exhibit reduced tolerance to ischemia and decreased transplant survival within ischemic muscle[251]. Similarly, older recipients have a diminished therapeutic response to receiving stem cells from donors of any age[251,254]. To overcome these effects related to cellular senescence, many strategies are being developed as recently reviewed[257].…”
Section: Ex Vivo Genetic Optimization Of Stem Cellsmentioning
Cell therapy has the potential to improve healing of ischemic heart, repopulate injured myocardium and restore cardiac function. The tremendous hope and potential of stem cell therapy is well understood, yet recent trials involving cell therapy for cardiovascular diseases have yielded mixed results with inconsistent data thereby readdressing controversies and unresolved questions regarding stem cell efficacy for ischemic cardiac disease treatment. These controversies are believed to arise by the lack of uniformity of the clinical trial methodologies, uncertainty regarding the underlying reparative mechanisms of stem cells, questions concerning the most appropriate cell population to use, the proper delivery method and timing in relation to the moment of infarction, as well as the poor stem cell survival and engraftment especially in a diseased microenvironment which is collectively acknowledged as a major hindrance to any form of cell therapy. Indeed, the microenvironment of the failing heart exhibits pathological hypoxic, oxidative and inflammatory stressors impairing the survival of transplanted cells. Therefore, in order to observe any significant therapeutic benefit there is a need to increase resilience of stem cells to death in the transplant microenvironment while preserving or better yet improving their reparative functionality. Although stem cell differentiation into cardiomyocytes has been observed in some instance, the prevailing reparative benefits are afforded through paracrine mechanisms that promote angiogenesis, cell survival, transdifferentiate host cells and modulate immune responses. Therefore, to maximize their reparative functionality, ex vivo manipulation of stem cells through physical, genetic and pharmacological means have shown promise to enable cells to thrive in the post-ischemic transplant microenvironment. In the present work, we will overview the current status of stem cell therapy for ischemic heart disease, discuss the most recurring cell populations employed, the mechanisms by which stem cells deliver a therapeutic benefit and strategies that have been used to optimize and increase survival and functionality of stem cells including ex vivo preconditioning with drugs and a novel “pharmaco-optimizer” as well as genetic modifications.
“…Recently, we evaluated the effect of cardiac‐resident BMSCs on the recovery of cardiac function after injury in aged animals . We found that BM reconstitution in old recipient mice with young donor cells improved cardiac functional recovery following injury.…”
Retinal ganglion cell apoptosis and optic nerve degeneration are prevalent in aged patients, which may be related to the decrease in bone marrow (BM) stem cell number/function because of the possible cross‐talk between the two organs. This pathological process is accelerated by retinal ischaemia‐reperfusion (I/R) injury. This study investigated whether young BM stem cells can regenerate and repair the aged retina after acute I/R injury. Young BM stem cell antigen 1 positive (Sca‐1+) or Sca‐1− cells were transplanted into lethally irradiated aged recipient mice to generate Sca‐1+ and Sca‐1− chimaeras, respectively. The animals were housed for 3 months to allow the young Sca‐1 cells to repopulate in the BM of aged mice. Retinal I/R was then induced by elevation of intraocular pressure. Better preservation of visual function was found in Sca‐1+ than Sca‐1− chimaeras 7 days after injury. More Sca‐1+ cells homed to the retina than Sca‐1− cells and more cells differentiated into glial and microglial cells in the Sca‐1+ chimaeras. After injury, Sca‐1+ cells in the retina reduced host cellular apoptosis, which was associated with higher expression of fibroblast growth factor 2 (FGF2) in the Sca‐1+ chimaeras. Young Sca‐1+ cells repopulated the stem cells in the aged retina and diminished cellular apoptosis after acute I/R injury through FGF2 and Akt signalling pathways.
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