Bryce H. Davis

Aging, Progenitor Cell Exhaustion, and Atherosclerosis

Background—Atherosclerosis is largely attributed to chronic vascular injury, as occurs with excess cholesterol; however, the effect of concomitant vascular aging remains unexplained. We hypothesize that the effect of time in atherosclerosis progression is related to obsolescence of endogenous progenitor cells that normally repair and rejuvenate the arteries. Methods and Results—Here we show that chronic treatment with bone marrow–derived progenitor cells from young nonatherosclerotic ApoE−/− mice prevents atherosclerosis progression in ApoE−/− recipients despite persistent hypercholesterolemia. In contrast, treatment with bone marrow cells from older ApoE−/− mice with atherosclerosis is much less effective. Cells with vascular progenitor potential are decreased in the bone marrow of aging ApoE−/− mice, but cells injected from donor mice engraft on recipient arteries in areas at risk for atherosclerotic injury. Conclusions—Our data indicate that progressive progenitor cell deficits may contribute to the development of atherosclerosis.

Comparison of Intracardiac Cell Transplantation: Autologous Skeletal Myoblasts Versus Bone Marrow Cells

An increasing number of patients living with cardiovascular disease (CVD) and still unacceptably high mortality created an urgent need to effectively treat and prevent disease-related events. Within the past 5 years, skeletal myoblasts (SKMBs) and bone marrow (or blood)-derived mononuclear cells (BMNCs) have demonstrated preclinical efficacy in reducing ischemia and salvaging already injured myocardium, and in preventing left ventricular (LV) remodeling, respectively. These findings have been translated into clinical trials, so far totaling over 200 patients for SKMBs and over 800 patients for BMNCs. These safety/feasibility and early phase II studies showed promising but somewhat conflicting symptomatic and functional improvements, and some safety concerns have arisen. However, the patient population, cell type, dose, time and mode of delivery, and outcome measures differed, making comparisons problematic. In addition, the mechanisms through which cells engraft and deliver their beneficial effects remain to be fully elucidated. It is now time to critically evaluate progress made and challenges encountered in order to select not only the most suitable cells for cardiac repair but also to define appropriate patient populations and outcome measures. Reiterations between bench and bedside will increase the likelihood of cell therapy success, reduce the time to development of combined of drug- and cell-based disease management algorithms, and offer these therapies to patients to achieve a greater reduction of symptoms and allow for a sustained improvement of quality of life.

SFRP2 Regulates Cardiomyogenic Differentiation by Inhibiting a Positive Transcriptional Autofeedback Loop of Wnt3a

Wnts comprise a family of 20 lipid‐modified glycoproteins in mammals and play critical roles during embryological development and organogenesis of several organ systems, including the heart. They are required for mesoderm formation and have been implicated in promoting cardiomyogenic differentiation of mammalian embryonic stem cells, but the underlying mechanisms regulating Wnt signaling during cardiomyogenesis remain poorly understood. In this report, we show that in a pluripotent mouse embryonal carcinoma stem cell line, SFRP2 inhibits cardiomyogenic differentiation by regulating Wnt3a transcription. SFRP2 inhibited early stages of cardiomyogenesis, preventing mesoderm specification and maintaining the cells in the undifferentiated state. Using a gain‐ and loss‐of‐function approach, we demonstrate that although addition of recombinant SFRP2 decreased Wnt3a transcription and cardiomyogenic differentiation, silencing of Sfrp2 led to enhanced Wnt3a transcription, mesoderm formation, and increased cardiomyogenesis. We show that the inhibitory effects of SFRP2 on Wnt transcription are secondary to interruption of a positive feedback effect of Wnt3a on its own transcription. Wnt3a increased its own transcription via the canonical pathway and TCF4 family of transcription factors, and the inhibitory effects of SFRP2 on Wnt3a transcription were associated with disruption of downstream canonical Wnt signaling. The inhibitory effects of Sfrp2 on Wnt3a expression identify Sfrp2 as a “checkpoint gene,” which exerts its control on cardiomyogenesis through regulation of Wnt3a transcription.

Abi3bp Is a Multifunctional Autocrine/Paracrine Factor that Regulates Mesenchymal Stem Cell Biology†

Mesenchymal stem cells (MSCs) transplanted into injured myocardium promote repair through paracrine mechanisms. We have previously shown that MSCs over‐expressing AKT1 (Akt‐MSCs) exhibit enhanced properties for cardiac repair. In this study, we investigated the relevance of Abi3bp toward MSC biology. Abi3bp formed extracellular deposits with expression controlled by Akt1 and ubiquitin‐mediated degradation. Abi3bp knockdown/knockout stabilized focal adhesions and promoted stress‐fiber formation. Furthermore, MSCs from Abi3bp knockout mice displayed severe deficiencies in osteogenic and adipogenic differentiation. Knockout or stable knockdown of Abi3bp increased MSC and Akt‐MSC proliferation, promoting S‐phase entry via cyclin‐d1, ERK1/2, and Src. Upon Abi3bp binding to integrin‐β1 Src associated with paxillin which inhibited proliferation. In vivo, Abi3bp knockout increased MSC number and proliferation in bone marrow, lung, and liver. In summary, we have identified a novel extracellular matrix protein necessary for the switch from proliferation to differentiation in MSCs. STEM Cells 2013;31:1669–1682

Transplantation of a mixed population of bone marrow-derived progenitor cells improves regional systolic function in a rabbit model of cryoinjured myocardium

a magnetic activated cell sorting technique. b2mcells (2.5 x 10 cells in 100 l) were transplanted seven days after infarction into a transmural myocardial scar induced by cryoinjury in lewis rats (n 9). control group #1(n 10) received a 100 l injection of normal saline, and control group #2 (n 15) received no injection. the b2mcells were labeled prior to transplantation using the membrane fluorescent intercalated dye pkh26-gl. repopulation was examined at 6 and 8 weeks after transplantation. differentiation of b2mcells into cardiac myocytes was determined by the co-localization of troponin and pkh26-gl to the same cell, utilizing immunohistochemistry, uv photo-microscopy and fluorescence confocal laser microscopy on 6 m serial sections. area of engraftment within the scar was calculated by planimetry. Results: the treatment group had multiple islands of de-novo formation of myocardium within the fibrous matrix of the transmural scar (mean area, 35% 4.2% of scar area at 6 and 8 weeks). these cells co-localized cardiac specific troponin and pkh26-gl. this staining pattern was not observed in the control groups. prior to transplantation, the b2mcells were troponin negative. Conclusion: This study demonstrates that B2Mcells represent a novel sub-population of bone marrow derived stem cells capable of successful and substantial engraftment in areas of transmural myocardial scar, with de-novo formation of cardiac myocytes.