Young Bone-Marrow Sca-1+ Stem Cells Rejuvenate the Aged Heart and Improve Function after Injury through PDGFRβ-Akt pathway

Li, Shuhong; Sun, Lu; Yang, Lei; Jiao, Li; Shao, Zhengbo; Du, Guoqing; Wu, Jun; Weisel, Richard D.; Li, Ren‐Ke

doi:10.1038/srep41756

Cited by 29 publications

(29 citation statements)

References 35 publications

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“…Furthermore, we demonstrated that the young BM cells from the reconstituted BM stably integrated in the aged myocardium prior to injury and were required for functional recovery after injury . Subsequently, we identified the stem cell antigen 1 (Sca‐1 + ) cell as the young BM cell type which had the greatest ability to home to the myocardium and protect the aged recipient mouse heart . Sca‐1 has been widely used as a marker to isolate haematopoietic stem cells.…”

Section: Introductionmentioning

confidence: 99%

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Young bone marrow Sca‐1 cells protect aged retina from ischaemia‐reperfusion injury through activation of FGF2

Shao

et al. 2018

J Cellular Molecular Medi

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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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Section: Introductionmentioning

confidence: 99%

“…15 Subsequently, we identified the stem cell antigen 1 (Sca-1 + ) cell as the young BM cell type which had the greatest ability to home to the myocardium and protect the aged recipient mouse heart. 16 Sca-1 has been widely used as a marker to isolate haematopoietic stem cells.…”

Section: Introductionmentioning

confidence: 99%

Young bone marrow Sca‐1 cells protect aged retina from ischaemia‐reperfusion injury through activation of FGF2

Shao

et al. 2018

J Cellular Molecular Medi

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“…To determine the extent to which inflammatory cell age affects myogenesis in old muscle, we used heterochronic bone marrow transplant. Sca-1 + enriched bone marrow (BM) cells from young or old GFP + donor mice were transplanted into lethally irradiated aged recipients as previously described 20 . Three months after BM transplant, hindlimb muscle was collected for comprehensive flow cytometry, gene expression and locomotive analysis.…”

Section: Resultsmentioning

confidence: 99%

Delineating the relationship between immune system aging and myogenesis in muscle repair

Tobin

Alibhai

Wlodarek

et al. 2020

Preprint

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12How aging affects the communication between immune cells and myoblasts during myogenesis 13 is unclear. We therefore investigated how aging impacts the cellular synchronization of these two 14 processes after muscle injury. Muscles of old mice (20 months) had chronic inflammation and 15 fewer satellite cells compared to young mice (3 months). After injury, young mice developed a 16 robust, but transient inflammatory response and a stepwise myogenic gene expression program. 17 These responses were impaired with age. Replacement of old bone marrow (BM) via 18 heterochronic bone marrow transplantation (BMT) increased muscle mass and performance on 19 locomotive and behavioural tests. After injury, Y-O BMT restored the immune cell and cytokine 20 profiles to a young phenotype and enhanced satellite cell activity while O-O BMT amplified a 21late-onset proinflammatory response. In vitro, conditioned media from young or old 22 macrophages had no effect or impaired myoblast proliferation, respectively. Thus, BM age 23 negatively affects myogenesis by inhibiting myoblast proliferation. 24 25 26 29proliferate and differentiate into mature muscle. The satellite cell population is limited, however, 30 as extensive activation caused by chronic injury may exhaust the stem cell pool 1 . Aging also 31 results in homeostatic and regenerative defects that leads to muscle loss via signals that are both 32 intrinsic and extrinsic to the satellite cell 2 . These signals ultimately impact absolute progenitor 33 cell number and function. 34Satellite cells become inherently defective with age, as transplantation of old satellite 35 cells to young muscle fail to repair muscle effectively 3,4 . Intrinsic factors that may account for 36 satellite cell aging include increased DNA damage, increased expression of cell cycle checkpoint 37 regulators such as p16 and p53, and loss of H3K27me3 histone methylation via reduced Ezh2 38 activity 5-7 . Aged muscle is subject to higher levels of muscle turnover by changes in the satellite 39 cell niche which may exhaust the stem cell pool 8 . With age, satellite cells also become prone to 40 higher levels of symmetric division, leading to fewer Pax7 + progenitor cells 4 , and geriatric 41 satellite cells may also enter an irreversible state of quiescence 7 . Myogenesis may also be 42 influenced by extrinsic factors in the blood that differ with age. This has been documented using 43 heterochronic parabiosis and blood transfusion 9-11 . Circulating factors, particularly members of 44 the TGF-β superfamily, increase with age and contribute to muscle wasting via upregulation of 45 cyclin dependent kinase inhibitors 12 . Despite moderate improvements in aged mice that receive 46 young blood 11 , the aged muscle microenvironment limits regenerative capacity. 47In addition to satellite cells, there are muscle-resident cells such as macrophages, 48 endothelial cells, Hoechst dye-excluding Side Population cells, and mesenchymal stem cells. 49Some of these cells arise from circulating cells which originate f...

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“…This minority cardiac cell population elicited its effects through paracrine‐directed improvement in survival, proliferation, and neovascularization. Subsequently, we found that stem cell antigen 1 (Sca‐1) cells were the key BM cell type involved in the rejuvenation of the aged heart (Li et al, ). We isolated Sca‐1 + or Sca‐1 − cells from the BM of young donor mice and infused them into lethally irradiated old recipients to generate Sca‐1 + or Sca‐1 − chimeras, respectively.…”

Section: Introductionmentioning

confidence: 99%

Long‐term repopulation of aged bone marrow stem cells using young Sca‐1 cells promotes aged heart rejuvenation

Dong

et al. 2019

Aging Cell

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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.

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Young Bone-Marrow Sca-1+ Stem Cells Rejuvenate the Aged Heart and Improve Function after Injury through PDGFRβ-Akt pathway

Cited by 29 publications

References 35 publications

Young bone marrow Sca‐1 cells protect aged retina from ischaemia‐reperfusion injury through activation of FGF2

Young bone marrow Sca‐1 cells protect aged retina from ischaemia‐reperfusion injury through activation of FGF2

Delineating the relationship between immune system aging and myogenesis in muscle repair

Long‐term repopulation of aged bone marrow stem cells using young Sca‐1 cells promotes aged heart rejuvenation

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