Restoration of aged hematopoietic cells by their young counterparts through instructive microvesicles release.

Steven J Greco,Pranela Rameshwar,Marina Gergues,Khadidiatou Guiro,Markos H El-Far,Michael J Schonning,Jean-Pierre Etchegaray,Robert J Donnelly,Yannick Kenfack,Lauren S Sherman,Seda Ayer,Garima Sinha,Sri Harika Pamarthi,Oleta A Sandiford

doi:10.18632/aging.203689

Steven J Greco, Pranela Rameshwar + Show 12 more

Open Access

https://doi.org/10.18632/aging.203689

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Abstract

This study addresses the potential to reverse age-associated morbidity by establishing methods to restore the aged hematopoietic system. Parabiotic animal models indicated that young secretome could restore aged tissues, leading us to establish a heterochronic transwell system with aged mobilized peripheral blood (MPB), co-cultured with young MPB or umbilical cord blood (UCB) cells. Functional studies and omics approaches indicate that the miRNA cargo of microvesicles (MVs) restores the aged hematopoietic system. The in vitro findings were validated in immune deficient (NSG) mice carrying an aged hematopoietic system, improving aged hallmarks such as increased lymphoid:myeloid ratio, decreased inflammation and cellular senescence. Elevated MYC and E2F pathways, and decreased p53 were key to hematopoietic restoration. These processes require four restorative miRs that target the genes for transcription/differentiation, namely PAX and phosphatase PPMIF. These miRs when introduced in aged cells were sufficient to restore the aged hematopoietic system in NSG mice. The aged MPBs were the drivers of their own restoration, as evidenced by the changes from distinct baseline miR profiles in MPBs and UCB to comparable expressions after exposure to aged MPBs. Restorative natural killer cells eliminated dormant breast cancer cells in vivo, indicating the broad relevance of this cellular paradigm - preventing and reversing age-associated disorders such as clearance of early malignancies and enhanced responses to vaccine and infection.

Highlights

Aging is a risk factor for chronic diseases, resulting in high morbidity, decreased quality of life and increased health care cost [1]
mobilized peripheral blood (MPB) are comprised of mixed cell subsets that include mature and immature hematopoietic cells
The hematopoietic effects by young MPBs on aged MPBs were studied in a transwell system in which the inner and outer wells contained equal amounts (107) of young and aged MPBs, respectively (Figure 1A)

Summary

Introduction

Aging is a risk factor for chronic diseases, resulting in high morbidity, decreased quality of life and increased health care cost [1]. Continuous intracellular stress leads to disrupted tissue physiology such as perturbated tissue homeostasis, stem cell exhaustion, and increased cellular senescence [2]. Cumulative ageassociated changes could be caused by external and replicative stress that alters the epigenetic dynamics [3]. These changes could predispose cells to oncogenic events, bypassing the default protection [4]. In the aged bone marrow www.aging-us.com (BM), the relationship between hematopoietic stem cells (HSCs) and their supporting niche cells such as stroma are functionally dysregulated [7, 8]. Single driver mutation in the aged hematopoietic cells can lead to the emergence of non-malignant clones of indeterminate potential (CHIP) thereby increasing the risk of hematological malignancy [16]. The aged neural system could influence BM functions, directly by innervation and indirectly by neurohormones [17,18,19]

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