Intramyocardial Transplantation of Circulating CD34+ cells: Source of Stem Cells for Myocardial Regeneration

Abstract A novel Hoechst 33342 dye efflux assay was recently developed that identifies a population of hematopoietic cells termed side population (SP) cells. In the bone marrow of multiple species, including mice and primates, the SP is composed primarily of CD34−cells, yet has many of the functional properties of hematopoietic stem cells (HSCs). This report characterizes SP cells from human umbilical cord blood (UCB). The SP in unfractionated UCB was enriched for CD34+ cells but also contained a large population of CD34− cells, many of which were mature lymphocytes. SP cells isolated from UCB that had been depleted of lineage-committed cells (Lin− UCB) contained CD34+ and CD34− cells in approximately equivalent proportions. Similar to previous descriptions of human HSCs, the CD34+Lin− SP cells were CD38dimHLA-DRdimThy-1dimCD45RA−CD71−and were enriched for myelo-erythroid precursors. In contrast, the CD34−Lin− SP cells were CD38−HLA-DR−Thy-1−CD71−and failed to generate myelo-erythroid progeny in vitro. The majority of these cells were CD7+CD11b+CD45RA+, as might be expected of early lymphoid cells, but did not express other lymphoid markers. The CD7+CD34−Lin− UCB SP cells did not proliferate in simple suspension cultures but did differentiate into natural killer cells when cultured on stroma with various cytokines. In conclusion, the human Lin− UCB SP contains both CD34+ multipotential stem cells and a novel CD7+CD34−Lin− lymphoid progenitor. This observation adds to the growing body of evidence that CD34− progenitors exist in humans.

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Long-Term Cryopreservation Does Not Affect Quality of Peripheral Blood Stem Cell Grafts: A Comparative Study of Native, Short-Term and Long-Term Cryopreserved Haematopoietic Stem Cells

Cell Transplantation ◽

10.1177/09636897211036004 ◽

2021 ◽

Vol 30 ◽

pp. 096368972110360

Author(s):

Daniel Lysak ◽

Michaela Brychtová ◽

Martin Leba ◽

Miroslava Čedíková ◽

Daniel Georgiev ◽

...

Keyword(s):

Stem Cells ◽

Stem Cell ◽

Statistical Significance ◽

Extended Period ◽

High Dose ◽

Atp Production ◽

Cd34 Cells ◽

Negative Effect

Cryopreserved haematopoietic progenitor cells are used to restore autologous haematopoiesis after high dose chemotherapy. Although the cells are routinely stored for a long period, concerns remain about the maximum storage time and the possible negative effect of storage on their potency. We evaluated the effect of cryopreservation on the quality of peripheral stem cell grafts stored for a short (3 months) and a long (10 years) period and we compared it to native products.The viability of CD34+ cells remained unaffected during storage, the apoptotic cells were represented up to 10% and did not differ between groups. The clonogenic activity measured by ATP production has decreased with the length of storage (ATP/cell 1.28 nM in native vs. 0.63 in long term stored products, P < 0.05). Only borderline changes without statistical significance were detected when examining mitochondrial and aldehyde dehydrogenase metabolic activity and intracellular pH, showing their good preservation during cell storage. Our experience demonstrates that cryostorage has no major negative effect on stem cell quality and potency, and therefore autologous stem cells can be stored safely for an extended period of at least 10 years. On the other hand, long term storage for 10 years and longer may lead to mild reduction of clonogenic capacity. When a sufficient dose of stem cells is infused, these changes will not have a clinical impact. However, in products stored beyond 10 years, especially when a low number of CD34+ cells is available, the quality of stem cell graft should be verified before infusion using the appropriate potency assays.

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Transplantation of allogeneic CD34+ peripheral blood stem cells in patients with advanced hematologic malignancy

Blood ◽

10.1182/blood.v88.11.4132.4132 ◽

1996 ◽

Vol 88 (11) ◽

pp. 4132-4138 ◽

Cited By ~ 5

Author(s):

WI Bensinger ◽

CD Buckner ◽

K Shannon-Dorcy ◽

S Rowley ◽

FR Appelbaum ◽

...

Keyword(s):

Stem Cells ◽

Body Weight ◽

Peripheral Blood ◽

Hematologic Malignancy ◽

Chronic Gvhd ◽

Allogeneic Transplantation ◽

Hematologic Malignancies ◽

Peripheral Blood Stem Cells ◽

Cd34 Cells ◽

Blood Stem Cells

Abstract Sixteen patients with advanced hematologic malignancies were transplanted with HLA-identical allogeneic peripheral blood stem cells (PBSCs) that were selected for CD34+ cells by an avidin-biotin immunoadsorption technique. The median age of patients was 48 years (range, 37 to 67). Patients received 12.0 or 13.2 Gy of total body irradiation followed by 120 mg/kg of cyclophosphamide. Normal donors received 16 mg/kg of granulocyte-colony stimulating factor on days 1 to 6 followed by PBSC harvests on days 4 to 7. PBSC harvests were processed each day on a single avidin-blotin column containing an antibody to the CD34 antigen and processed cells were infused without cryopreservation daily for 4 consecutive days. Prophylaxis against graft-versus-host disease (GVHD) consisted of cyclosporine alone for 5 patients and CSA plus methotrexate for 11 patients. A median of 18.64 (6.74 to 34.97) x 10(8) CD34+ cells/kg patient body weight were collected from each donor. A median of 8.96 (2.62 to 17.34) x 10(8) CD34+ cells/kg patient body weight were recovered after avidin-biotin adsorption which represented a median CD34+ cell yield of 53% (18% to 77%) with a median purity of 62% (34% to 82%). There was a reduction in CD3+ cells from a median of 557.26 (227.73 to 677.77) x 106/kg to 0.73 x 10(4)/kg (0.40 to 3.65), in CD4+ cells from 351.72 (194.47 to 520.11) x 10(6)/kg to 0.40 (0.15 to 1.03) x 10(4)/kg and in CD8+ cells from 169.74 (53.34 to 325.83) x 10(6)/ kg to 0.32 (0.12 to 2.71) x 10(4)/kg representing a median 2.8 (2.19 to 3.14) log reduction in T cells. One patient died of infection on day 3 posttransplant and was unevaluable for recovery of neutrophils. The median day to recovery of 500 neutrophils/mL was 15 (8 to 26) in the remaining 15 patients. Six of 16 patients falled to achieve a platelet count of 20,000/mL before death on days 3 to 97 of transplant-related complications. The median day to achieving platelets of 20,000 mL in the remaining 10 patients was 11 (7 to 31). Eight of 16 patients (50%) died between 3 and 97 days posttransplant, 7 of transplant-related causes, and 1 of progressive disease. Grade 2–4 acute GVHD occurred in 12 out of 14 (86%) and grades 3–4 in 6 out of 14 (43%) evaluable patients. Six of 8 evaluable patients developed clinical chronic GVHD and 1 developed subclinical chronic GVHD. Bone marrow and/or peripheral blood chimerism studies in 12 evaluable patients showed 97% to 100% donor type in 11 patients with 1 patient in relapse showing 40% donor cells 60 to 90 days posttransplant. Four of 16 patients (25%) are alive and disease-free 312 to 576 days after transplant. There were no episodes of graft failure or rejection. This study shows that allogeneic transplantation using CD34+ selected PBSC results in prompt and sustained engraftment. CD34+ selection, as employed in this preliminary study, however, resulted in an apparently higher rate of acute and chronic GVHD. However, The sample size is quite small and precludes a more definitive conclusion regarding GVHD.

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Plerixafor and G-CSF versus placebo and G-CSF to mobilize hematopoietic stem cells for autologous stem cell transplantation in patients with multiple myeloma

Blood ◽

10.1182/blood-2008-08-174946 ◽

2009 ◽

Vol 113 (23) ◽

pp. 5720-5726 ◽

Cited By ~ 492

Author(s):

John F. DiPersio ◽

Edward A. Stadtmauer ◽

Auayporn Nademanee ◽

Ivana N. M. Micallef ◽

Patrick J. Stiff ◽

...

Keyword(s):

Stem Cells ◽

Multiple Myeloma ◽

Hematopoietic Stem Cells ◽

Primary Endpoint ◽

Controlled Study ◽

Double Blind ◽

Hematopoietic Stem ◽

Injection Site Reactions ◽

Cd34 Cells ◽

Stimulating Factor

Abstract This phase 3, multicenter, randomized (1:1), double-blind, placebo-controlled study evaluated the safety and efficacy of plerixafor with granulocyte colony-stimulating factor (G-CSF) in mobilizing hematopoietic stem cells in patients with multiple myeloma. Patients received G-CSF (10 μg/kg) subcutaneously daily for up to 8 days. Beginning on day 4 and continuing daily for up to 4 days, patients received either plerixafor (240 μg/kg) or placebo subcutaneously. Starting on day 5, patients began daily apheresis for up to 4 days or until more than or equal to 6 × 106 CD34+ cells/kg were collected. The primary endpoint was the percentage of patients who collected more than or equal to 6 × 106 CD34+ cells/kg in less than or equal to 2 aphereses. A total of 106 of 148 (71.6%) patients in the plerixafor group and 53 of 154 (34.4%) patients in the placebo group met the primary endpoint (P < .001). A total of 54% of plerixafor-treated patients reached target after one apheresis, whereas 56% of the placebo-treated patients required 4 aphereses to reach target. The most common adverse events related to plerixafor were gastrointestinal disorders and injection site reactions. Plerixafor and G-CSF were well tolerated, and significantly more patients collected the optimal CD34+ cell/kg target for transplantation earlier compared with G-CSF alone. This study is registered at www.clinicaltrials.gov as #NCT00103662.

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Impact of Induction Treatment on Stem Cell Collection: A COVID Related Study

Blood ◽

10.1182/blood-2021-149812 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 4848-4848

Author(s):

Brad Rybinski ◽

Ashraf Z. Badros ◽

Aaron P. Rapoport ◽

Mehmet Hakan Kocoglu

Keyword(s):

Stem Cells ◽

Stem Cell ◽

Research Funding ◽

Median Number ◽

Cell Transplant ◽

Cd34 Cells ◽

Significant Difference ◽

Number Of Cycles ◽

Time Required ◽

Stem Cell Collection

Abstract Introduction: Standard induction therapy for multiple myeloma consists of 3-6 cycles of bortezomib, lenalidomide, and dexamethasone (VRd) or carfilzomib, lenalidomide and dexamethasone (KRd). Receiving greater than 6 cycles of a lenalidomide containing regimen is thought to negatively impact the ability to collect sufficient CD34+ stem cells for autologous stem cell transplant (Kumar, Dispenzieri et al. 2007, Bhutani, Zonder et al. 2013). Due to the COVID-19 pandemic, at least 20 patients at University of Maryland Greenebaum Comprehensive Cancer Center (UMGCC) had transplant postponed, potentially resulting in prolonged exposure to lenalidomide containing induction regimens. Here, in the context of modern stem cell mobilization methods, we describe a retrospective study that suggests prolonged induction does not inhibit adequate stem cell collection for transplant. Methods: By chart review, we identified 56 patients with multiple myeloma who received induction with VRd or KRd and underwent apheresis or stem cell transplant at UMGCC between 10/1/19 and 10/1/20. Patients were excluded if they received more than 2 cycles of a different induction regimen, had a past medical history of an inborn hematological disorder, or participated in a clinical trial of novel stem cell mobilization therapy. We defined 1 cycle of VRd or KRd as 1 cycle of "lenalidomide containing regimen". In accordance with routine clinical practice, we defined standard induction as having received 3-6 cycles of lenalidomide containing regimen and prolonged induction as having received 7 or more cycles. Results: 29 patients received standard induction (Standard induction cohort) and 27 received prolonged induction (Prolonged induction cohort) with lenalidomide containing regimens. The median number of cycles received by the Standard cohort was 6 (range 4-6), and the median number of cycles received by the Prolonged cohort was 8 (range 7-13). The frequency of KRd use was similar between patients who received standard induction and prolonged induction (27.58% vs. 25.93%, respectively). Standard induction and Prolonged induction cohorts were similar with respect to clinical characteristics (Fig 1), as well as the mobilization regimen used for stem cell collection (p = 0.6829). 55/56 patients collected sufficient stem cells for 1 transplant (≥ 4 x 10 6 CD34 cells/kg), and 40/56 patients collected sufficient cells for 2 transplants (≥ 8 x 10 6 CD34 cells/kg). There was no significant difference in the total CD34+ stem cells collected at completion of apheresis between standard and prolonged induction (10.41 and 10.45 x 10 6 CD34 cells/kg, respectively, p = 0.968, Fig 2). Furthermore, there was no significant correlation between the number of cycles of lenalidomide containing regimen a patient received and total CD34+ cells collected (R 2 = 0.0073, p = 0.5324). Although prolonged induction did not affect final stem yield, prolonged induction could increase the apheresis time required for adequate collection or result in more frequent need for plerixafor rescue. There was no significant difference in the total number of stem cells collected after day 1 of apheresis between patients who received standard or prolonged induction (8.72 vs. 7.96 x 10 6 cells/kg, respectively, p = 0.557). However, patients who received prolonged induction were more likely to require 2 days of apheresis (44% vs. 25%, p = 0.1625) and there was a trend toward significance in which patients who received prolonged induction underwent apheresis longer than patients who received standard induction (468 vs 382 minutes, respectively, p = 0.0928, Fig 3). In addition, longer apheresis time was associated with more cycles of lenalidomide containing regimen, which neared statistical significance (R 2 = 0.0624, p = 0.0658, Fig 4). There was no significant difference between standard and prolonged induction with respect to the frequency of plerixafor rescue. Conclusions: Prolonged induction with lenalidomide containing regimens does not impair adequate stem cell collection for autologous transplant. Prolonged induction may increase the apheresis time required to collect sufficient stem cells for transplant, but ultimately clinicians should be re-assured that extending induction when necessary is not likely to increase the risk of collection failure. Figure 1 Figure 1. Disclosures Badros: Janssen: Research Funding; J&J: Research Funding; BMS: Research Funding; GlaxoSmithKline: Research Funding.

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The Integrated Stress Response Activity Marks Stem Cells in Normal Hematopoiesis and Leukemia

Blood ◽

10.1182/blood-2018-99-110819 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 1276-1276

Author(s):

Nathan Mbong ◽

John E. Dick ◽

Peter Van Galen ◽

Antonija Kreso ◽

Elvin Wagenblast ◽

...

Keyword(s):

Stem Cells ◽

Amino Acid ◽

Stress Response ◽

Nutrient Deprivation ◽

Integrated Stress Response ◽

Amino Acid Deprivation ◽

Term Survival ◽

Hematopoietic Stem ◽

Cd34 Cells ◽

Human Hscs

Abstract Lifelong maintenance of the blood system requires equilibrium between clearance of damaged hematopoietic stem cells (HSCs) and long-term survival of the HSC pool. Perturbations of cellular homeostasis such as nutrient deprivation, irradiation, and endoplasmic reticulum stress can result in HSC loss. However, HSCs must survive low-level stressors in order to sustain lifelong replenishment of the hematopoietic system. It is poorly understood how human HSCs balance apoptosis with survival in the context of basal stress, and how adaptive signalling is regulated in leukemia stem cells (LSCs). The Integrated Stress Response (ISR) is an adaptive pathway that can protect cells against stressors such as ROS, nutrient deprivation and misfolded proteins. To assess the expression levels of key ISR pathway components, we analyzed the proteome of purified human HSCs and progenitor cells from cord blood (CB). Quantitative label-free mass spectrometry revealed lower expression of eIF2α, eIF2β and eIF2γ subunits in HSCs compared to downstream progenitors. Furthermore, activated-transcription factor 4 (ATF4) mRNA is highly expressed in HSCs compared to progenitors. Similar to our findings in normal CB cells, analysis of acute myeloid leukemia (AML) patient samples revealed lower protein levels of eIF2α, eIF2β and eIF2γ in phenotypically primitive (CD34+CD38-) compared to differentiated (CD34+CD38+) AML cell populations. These results suggest that primitive cells in normal hematopoiesis and AML are primed for ISR activation.To assess ISR activity in human HSPCs, we used an ATF4 lentiviral reporter (ATF4rep) that measures ISR-induced ATF4 translation. We subjected ATF4rep-transduced CD34+ CB cells to hypoxia and amino acid deprivation, and found that valine depletion strongly induced ATF4rep activity. ATF4rep upregulation was abolished in the presence of an eIF2αS52A mutant that cannot be phosphorylated. Furthermore, knockdown of eIF2α, eIF2β or eIF2γ subunits in CD34+ CB cells increased ATF4rep activity. Thus, low levels of eIF2α, eIF2β or eIF2γ result in efficient ATF4 translation, and nutrient deprivation upregulates ATF4 through eIF2α phosphorylation. We assessed the effect of ATF4 upregulation on CB cell proliferation and survival. Following knockdown of ATF4 mRNA in CD34+ CB cells, the cells were incubated in valine deficient media to induce translational upregulation of ATF4. Valine depletion of shCTRL-transduced cells for 2 days did not affect proliferation or apoptosis, as measured by EdU incorporation or Annexin-V. In contrast, valine depletion of shATF4-transduced cells resulted in decreased proliferation (2-fold, P = 0.0004) and increased apoptosis (4-fold, P < 0.0001,). Thus, ATF4 promotes survival of primitive CD34+ CB cells undergoing valine depletion.We performed in vivo xenograft studies to examine the ISR activity in the best available setting to approximate homeostatic conditions for human HSPCs. Transplantation of ATF4rep-transduced CB cells showed that human HSPCs in the mouse bone marrow maintained a 2.4-fold higher ATF4rep activity compared to downstream progenitors (P = 0.0002). ATF4rep activity further declined in mature monocytes, granulocytes and B-cells (13-fold, P < 0.0001). To determine if high ISR activity is associated with improved HSC function, we transplanted lin- CB cells expressing high ATF4rep activity (GFP-high) and low ATF4rep activity (GFP-low) into mice. The level of engraftment as well as the number of engrafted mice was increased from GFP-high cells compared to GFP-low cells (P = 0.001). The hierarchical structure of normal hematopoiesis is partially maintained in AML. We evaluated ATF4rep expression in the malignant hierarchy and found that 4/5 patient samples had higher ATF4rep expression in CD34+ cells compared to CD34- cells. Furthermore, serial transplantation of ATF4rep-transduced cells showed higher engraftment from GFP-high compared to GFP-low cells ( P < 0.0001). Thus, primary human AML cells that possess high ISR activity are enriched for LSC function.Our data establish that the adaptive ISR pathway plays a key role in maintaining homeostasis of normal and malignant stem cells. We show that Amino acid deprivation activates the ISR in human HSPCs resulting in ATF4-dependent pro-survival signals. In an unperturbed state, HSCs are in a state of primed ISR activity, mechanistically maintained by eIF2 scarcity and high ATF4 levels. Disclosures No relevant conflicts of interest to declare.

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Very Small Embryonic-Like Stem Cells, Endothelial Progenitor Cells, and Different Monocyte Subsets Are Effectively Mobilized in Acute Lymphoblastic Leukemia Patients after G-CSF Treatment

Stem Cells International ◽

10.1155/2018/1943980 ◽

2018 ◽

Vol 2018 ◽

pp. 1-8 ◽

Cited By ~ 4

Author(s):

Andrzej Eljaszewicz ◽

Lukasz Bolkun ◽

Kamil Grubczak ◽

Malgorzata Rusak ◽

Tomasz Wasiluk ◽

...

Keyword(s):

Stem Cells ◽

Stem Cell ◽

Acute Lymphoblastic Leukemia ◽

Progenitor Cells ◽

Endothelial Progenitor Cells ◽

Lymphoblastic Leukemia ◽

Monocyte Subsets ◽

Endothelial Progenitor ◽

Hematopoietic Stem ◽

Cd34 Cells

Background. Acute lymphoblastic leukemia (ALL) is a malignant disease of lymphoid progenitor cells. ALL chemotherapy is associated with numerous side effects including neutropenia that is routinely prevented by the administration of growth factors such as granulocyte colony-stimulating factor (G-CSF). To date, the effects of G-CSF treatment on the level of mobilization of different stem and progenitor cells in ALL patients subjected to clinically effective chemotherapy have not been fully elucidated. Therefore, in this study we aimed to assess the effect of administration of G-CSF to ALL patients on mobilization of other than hematopoietic stem cell (HSCs) subsets, namely, very small embryonic-like stem cells (VSELs), endothelial progenitor cells (EPCs), and different monocyte subsets. Methods. We used multicolor flow cytometry to quantitate numbers of CD34+ cells, hematopoietic stem cells (HSCs), VSELs, EPCs, and different monocyte subsets in the peripheral blood of ALL patients and normal age-matched blood donors. Results. We showed that ALL patients following chemotherapy, when compared to healthy donors, presented with significantly lower numbers of CD34+ cells, HSCs, VSELs, and CD14+ monocytes, but not EPCs. Moreover, we found that G-CSF administration induced effective mobilization of all the abovementioned progenitor and stem cell subsets with high regenerative and proangiogenic potential. Conclusion. These findings contribute to better understanding the beneficial clinical effect of G-CSF administration in ALL patients following successful chemotherapy.

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Abstract 256: Paracrine miRNA-Crosstalk Between Human CD34+ Stem Cells and Selective Myocardial Cells Via Therapeutic Exosomes Promotes Repair of the Ischemic Heart

Circulation Research ◽

10.1161/res.115.suppl_1.256 ◽

2014 ◽

Vol 115 (suppl_1) ◽

Author(s):

Susmita Sahoo ◽

David Kim ◽

Sol Misener ◽

Christine E Kamide ◽

Douglas E Vaughan ◽

...

Keyword(s):

Gene Expression ◽

Stem Cells ◽

Endothelial Cells ◽

Ischemic Myocardium ◽

Ischemic Heart ◽

Target Cells ◽

Myocardial Repair ◽

Human Cd34 ◽

Therapeutic Benefits ◽

Cd34 Cells

Introduction: Earlier, in a first study of its kind, we have demonstrated a novel mechanism that therapeutically significant human CD34+ stem cells secrete membrane bound nano-vesicles called exosomes (CD34Exo). CD34Exo are angiogenic and constitute a critical component of the pro-angiogenic paracrine activity of the cells. Further, when transplanted locally, cell-free CD34Exo induce ischemic tissue repair in a murine hindlimb ischemia model. Here, we hypothesize that exosomes released via paracrine secretion from human CD34+ cells mediate myocardial repair by direct transfer of microRNAs to target cells in the heart. Methods and Results: When injected into mouse ischemic myocardium, cell-free CD34Exo replicated the therapeutic activity of human CD34+ cells by significantly improving ischemia (ejection fraction, 42±4 v 22±6%; capillary density, 113±7 v 66±6/HPF; fibrosis, 27±2 v 48±7%; p<0.05, n=7-12) compared with PBS control. Interestingly, confocal imaging and flow cytometry analyses of the exosomes-injected ischemic myocardial tissue revealed that CD34Exo was selectively internalized into endothelial cells and cardiomyocytes. CD34Exo, which is enriched with miR126, induced the expression of miR126 and several pro-angiogenic mRNAs in the exosomes-treated ischemic myocardium, but did not affect the endogenous synthesis of miR126. CD34Exo lacking miR126 had decreased angiogenic activity in vitro and decreased proangiogenic gene expression in vivo indicating that miR126 is important for CD34Exo function. Imaging using fluorescent miR126 confirms that CD34Exo directly transferred miR126 and possibly other yet to be identified moieties from its cargo, selectively to endothelial cells and cardiomyocytes in the ischemic heart. Conclusion: Our results reveal a novel molecular and trafficking mechanism of CD34Exo that may be responsible for intercellular transfer of genetic information such as miRNAs from human CD34+ stem cells, selectively to endothelial cells and cardiomyocytes inducing changes in gene expression, angiogenesis and myocardial recovery. Exosomes-shuttled miRNAs may signify amplification of stem cell function and may explain the therapeutic benefits associated with human CD34+ cell therapy.

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Mesenchymal stem cells seeded onto nanofiber scaffold for myocardial regeneration

Biotechnic & Histochemistry ◽

10.1080/10520295.2021.1979251 ◽

2021 ◽

pp. 1-12

Author(s):

Mohamed S. Kishta ◽

Hanaa H. Ahmed ◽

Mohamed A. M. Ali ◽

Hadeer A. Aglan ◽

Mohamed Ragaa Mohamed

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Myocardial Regeneration ◽

Nanofiber Scaffold

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Abstract 258: Pitx2 Promotes Murine Myocardial Regeneration after Myocardial Injury

Circulation Research ◽

10.1161/res.115.suppl_1.258 ◽

2014 ◽

Vol 115 (suppl_1) ◽

Author(s):

GE TAO ◽

Elzbieta Klysik ◽

Yuka Morikawa ◽

James F Martin

Keyword(s):

Myocardial Infarction ◽

Stem Cells ◽

Myocardial Injury ◽

De Novo ◽

The United States ◽

Myocardial Regeneration ◽

Mouse Heart ◽

Specific Cell ◽

Regulation Of Transcription ◽

Regenerative Therapy

Myocardial infarction is the leading cause of morbidity and mortality in the United States. Compromised myocardial function, due to the lack of self-renewal capacity in mature hearts, is a major reason for heart failure. Available therapies can only ameliorate, but not reverse the loss of functional myocardium. With heart transplantation as the only available cure, design of an effective regenerative therapy has become imperative for cardiovascular research. To repopulate the heart with de novo cardiomyocytes, most attempts have been based on the transplantation of cardiac, non-cardiac stem cells or their derivatives, however a more profound knowledge of stem cells is required for achieving significant progress. Meanwhile, triggering endogenous regenerative capacity is a compelling strategy for cardiac repair. It has been reported that proliferation of pre-existing cardiomyocytes strongly contributes to regeneration. Thus, efforts have been made to reintroduce mature cardiomyocytes into mitotic cycle. The mechanisms underlying the proliferation of cardiomyocytes during development and their homeostasis during adulthood are not fully understood, but likely require tight regulation of transcription factors in specific cell types. We have previously shown that the mouse Hippo kinase cascade is a major heart-size control pathway during development. In addition, activation of Yap, a transcriptional cofactor inhibited by Hippo, by genetically disrupting Hippo signaling is sufficient to induce juvenile and adult myocardial regeneration after surgery-induced myocardial infarction. Here we identified the paired-like homeodomain transcription factor 2 (pitx2) as a potential downstream target and cofactor of Yap in mouse heart. Our data indicates that Pitx2 expression is induced by myocardial injury, and is required for neonatal myocardial regeneration in a postnatal day 1 (P1) apex resection model. Further studies show that over-expression of pitx2 in adult cardiomyocytes is sufficient to promote the restoration of myocardial structure and function after myocardial infarction. Together, we show that pitx2 is a new manipulator of myocardial regeneration and could serve as a novel therapeutic target in cardiac regenerative therapy.

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