The University of Southampton
University of Southampton Institutional Repository

POT1a deficiency in mesenchymal niches perturbs B-lymphopoiesis

POT1a deficiency in mesenchymal niches perturbs B-lymphopoiesis
POT1a deficiency in mesenchymal niches perturbs B-lymphopoiesis

Protection of telomeres 1a (POT1a) is a telomere binding protein. A decrease of POT1a is related to myeloid-skewed haematopoiesis with ageing, suggesting that protection of telomeres is essential to sustain multi-potency. Since mesenchymal stem cells (MSCs) are a constituent of the hematopoietic niche in bone marrow, their dysfunction is associated with haematopoietic failure. However, the importance of telomere protection in MSCs has yet to be elucidated. Here, we show that genetic deletion of POT1a in MSCs leads to intracellular accumulation of fatty acids and excessive ROS and DNA damage, resulting in impaired osteogenic-differentiation. Furthermore, MSC-specific POT1a deficient mice exhibited skeletal retardation due to reduction of IL-7 producing bone lining osteoblasts. Single-cell gene expression profiling of bone marrow from POT1a deficient mice revealed that B-lymphopoiesis was selectively impaired. These results demonstrate that bone marrow microenvironments composed of POT1a deficient MSCs fail to support B-lymphopoiesis, which may underpin age-related myeloid-bias in haematopoiesis.

Animals, Mice, Aging, Cell Differentiation, Lymphopoiesis/genetics, Telomere/genetics, Telomere-Binding Proteins/genetics
2399-3642
996
Nakashima, Kentaro
476152c8-a532-4310-930b-7f5743438d17
Kunisaki, Yuya
c9875902-7b58-4017-93fe-b5814c1aae96
Hosokawa, Kentaro
8868fb61-102f-4776-9270-77bf23b52f65
Gotoh, Kazuhito
9a635290-0de7-413e-a54b-795c5360d516
Yao, Hisayuki
46272fd3-9c55-42a3-b5bc-95b4816c06ae
Yuta, Ryosuke
9001f6bf-b8b9-42a9-873a-0cfff2e939a5
Semba, Yuichiro
55f97152-ff8b-47de-893f-80bf7d7dfc33
Nogami, Jumpei
d48f5678-dea5-4237-afa8-219f720aacbf
Kikushige, Yoshikane
9e0357ae-6424-40a4-b04d-db2466e83faf
Stumpf, Patrick S.
dfdb286c-b321-46d3-8ba2-85b3b4a7f092
MacArthur, Ben D.
2c0476e7-5d3e-4064-81bb-104e8e88bb6b
Kang, Dongchon
682861dc-3c59-4046-ace4-e42d4ad076d2
Akashi, Koichi
c76de2d9-ffa4-4dbd-b63d-a6f27d63b270
Ohga, Shouichi
c56ae65a-ad6b-45bf-a66f-7751f12ba57a
Arai, Fumio
6f499041-0756-4b99-a40a-baaa9111221e
Nakashima, Kentaro
476152c8-a532-4310-930b-7f5743438d17
Kunisaki, Yuya
c9875902-7b58-4017-93fe-b5814c1aae96
Hosokawa, Kentaro
8868fb61-102f-4776-9270-77bf23b52f65
Gotoh, Kazuhito
9a635290-0de7-413e-a54b-795c5360d516
Yao, Hisayuki
46272fd3-9c55-42a3-b5bc-95b4816c06ae
Yuta, Ryosuke
9001f6bf-b8b9-42a9-873a-0cfff2e939a5
Semba, Yuichiro
55f97152-ff8b-47de-893f-80bf7d7dfc33
Nogami, Jumpei
d48f5678-dea5-4237-afa8-219f720aacbf
Kikushige, Yoshikane
9e0357ae-6424-40a4-b04d-db2466e83faf
Stumpf, Patrick S.
dfdb286c-b321-46d3-8ba2-85b3b4a7f092
MacArthur, Ben D.
2c0476e7-5d3e-4064-81bb-104e8e88bb6b
Kang, Dongchon
682861dc-3c59-4046-ace4-e42d4ad076d2
Akashi, Koichi
c76de2d9-ffa4-4dbd-b63d-a6f27d63b270
Ohga, Shouichi
c56ae65a-ad6b-45bf-a66f-7751f12ba57a
Arai, Fumio
6f499041-0756-4b99-a40a-baaa9111221e

Nakashima, Kentaro, Kunisaki, Yuya, Hosokawa, Kentaro, Gotoh, Kazuhito, Yao, Hisayuki, Yuta, Ryosuke, Semba, Yuichiro, Nogami, Jumpei, Kikushige, Yoshikane, Stumpf, Patrick S., MacArthur, Ben D., Kang, Dongchon, Akashi, Koichi, Ohga, Shouichi and Arai, Fumio (2023) POT1a deficiency in mesenchymal niches perturbs B-lymphopoiesis. Communications Biology, 6 (1), 996, [996]. (doi:10.1038/s42003-023-05374-0).

Record type: Article

Abstract

Protection of telomeres 1a (POT1a) is a telomere binding protein. A decrease of POT1a is related to myeloid-skewed haematopoiesis with ageing, suggesting that protection of telomeres is essential to sustain multi-potency. Since mesenchymal stem cells (MSCs) are a constituent of the hematopoietic niche in bone marrow, their dysfunction is associated with haematopoietic failure. However, the importance of telomere protection in MSCs has yet to be elucidated. Here, we show that genetic deletion of POT1a in MSCs leads to intracellular accumulation of fatty acids and excessive ROS and DNA damage, resulting in impaired osteogenic-differentiation. Furthermore, MSC-specific POT1a deficient mice exhibited skeletal retardation due to reduction of IL-7 producing bone lining osteoblasts. Single-cell gene expression profiling of bone marrow from POT1a deficient mice revealed that B-lymphopoiesis was selectively impaired. These results demonstrate that bone marrow microenvironments composed of POT1a deficient MSCs fail to support B-lymphopoiesis, which may underpin age-related myeloid-bias in haematopoiesis.

Text
s42003-023-05374-0 - Version of Record
Available under License Creative Commons Attribution.
Download (5MB)

More information

Accepted/In Press date: 18 September 2023
e-pub ahead of print date: 29 September 2023
Published date: 29 September 2023
Additional Information: Funding Information: This study was supported by Grants-in-Aid for Scientific Research from the Japan Society for the Promotion of Science (grants 20H03711 and 23H02935 to A.F.; 21H02950 to Y.Kunisaki), and AMED under Grant Number JP19bm0404052h0001 to A.F. We would like to acknowledge all our colleagues in Dr. Kang’s, Dr. Akashi’s and Dr. Arai’s laboratory for their support throughout this project. We appreciate the technical support from the Research Support Centre, Graduate School of Medical Sciences, Kyushu University, and from the Medical Institute of Bioregulation, Kyushu University. © 2023. Springer Nature Limited.
Keywords: Animals, Mice, Aging, Cell Differentiation, Lymphopoiesis/genetics, Telomere/genetics, Telomere-Binding Proteins/genetics

Identifiers

Local EPrints ID: 484434
URI: http://eprints.soton.ac.uk/id/eprint/484434
ISSN: 2399-3642
PURE UUID: 96a1507d-ff95-453d-b573-f1135e0850ac
ORCID for Patrick S. Stumpf: ORCID iD orcid.org/0000-0003-0862-0290
ORCID for Ben D. MacArthur: ORCID iD orcid.org/0000-0002-5396-9750

Catalogue record

Date deposited: 16 Nov 2023 12:07
Last modified: 06 Jun 2024 01:39

Export record

Altmetrics

Contributors

Author: Kentaro Nakashima
Author: Yuya Kunisaki
Author: Kentaro Hosokawa
Author: Kazuhito Gotoh
Author: Hisayuki Yao
Author: Ryosuke Yuta
Author: Yuichiro Semba
Author: Jumpei Nogami
Author: Yoshikane Kikushige
Author: Patrick S. Stumpf ORCID iD
Author: Dongchon Kang
Author: Koichi Akashi
Author: Shouichi Ohga
Author: Fumio Arai

Download statistics

Downloads from ePrints over the past year. Other digital versions may also be available to download e.g. from the publisher's website.

View more statistics

Atom RSS 1.0 RSS 2.0

Contact ePrints Soton: eprints@soton.ac.uk

ePrints Soton supports OAI 2.0 with a base URL of http://eprints.soton.ac.uk/cgi/oai2

This repository has been built using EPrints software, developed at the University of Southampton, but available to everyone to use.

We use cookies to ensure that we give you the best experience on our website. If you continue without changing your settings, we will assume that you are happy to receive cookies on the University of Southampton website.

×