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BMP signaling is required for postnatal murine hematopoietic stem cell self-renewal

Warsi, Sarah LU ; Blank, Ulrika ; Dahl, Maria LU ; Min Grahn, Tan Hooi LU orcid ; Schmiderer, Ludwig LU ; Andradottir, Silja LU and Karlsson, Stefan LU orcid (2021) In Haematologica 106(8). p.2203-2214
Abstract

Life-long production of blood from hematopoietic stem cells (HSC) is a process of strict modulation. Intrinsic and extrinsic signals govern fate options like self-renewal – a cardinal feature of HSC. Bone morphogenetic proteins (BMP) have an established role in embryonic hematopoiesis, but less is known about its functions in adulthood. Previously, SMAD-mediated BMP signaling has been proven dispensable for HSC. However, the BMP type-II receptor (BMPR-II) is highly expressed in HSC, leaving the possibility that BMP function via alternative pathways. Here, we establish that BMP signaling is required for self-renewal of adult HSC. Through conditional knockout we show that BMPR-II deficient HSC have impaired self-renewal and regenerative... (More)

Life-long production of blood from hematopoietic stem cells (HSC) is a process of strict modulation. Intrinsic and extrinsic signals govern fate options like self-renewal – a cardinal feature of HSC. Bone morphogenetic proteins (BMP) have an established role in embryonic hematopoiesis, but less is known about its functions in adulthood. Previously, SMAD-mediated BMP signaling has been proven dispensable for HSC. However, the BMP type-II receptor (BMPR-II) is highly expressed in HSC, leaving the possibility that BMP function via alternative pathways. Here, we establish that BMP signaling is required for self-renewal of adult HSC. Through conditional knockout we show that BMPR-II deficient HSC have impaired self-renewal and regenerative capacity. BMPR-II deficient cells have reduced p38 activation, implying that non-SMAD pathways operate downstream of BMP in HSC. Indeed, a majority of primitive hematopoietic cells do not engage in SMAD-mediated responses downstream of BMP in vivo. Furthermore, deficiency of BMPR-II results in increased expression of TJP1, a known regulator of self-renewal in other stem cells, and knockdown of TJP1 in primitive hematopoietic cells partly rescues the BMPR-II null phenotype. This suggests TJP1 may be a universal stem cell regulator. In conclusion, BMP signaling, in part mediated through TJP1, is required endogenously by adult HSC to maintain self-renewal capacity and proper resilience of the hematopoietic system during regeneration.

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author
; ; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Haematologica
volume
106
issue
8
pages
12 pages
publisher
Ferrata Storti Foundation
external identifiers
  • pmid:32675226
  • scopus:85111086548
ISSN
0390-6078
DOI
10.3324/haematol.2019.236125
language
English
LU publication?
yes
id
a2852ad0-36db-4299-b65b-c677217b009b
date added to LUP
2022-03-21 10:30:01
date last changed
2025-03-14 15:29:00
@article{a2852ad0-36db-4299-b65b-c677217b009b,
  abstract     = {{<p>Life-long production of blood from hematopoietic stem cells (HSC) is a process of strict modulation. Intrinsic and extrinsic signals govern fate options like self-renewal – a cardinal feature of HSC. Bone morphogenetic proteins (BMP) have an established role in embryonic hematopoiesis, but less is known about its functions in adulthood. Previously, SMAD-mediated BMP signaling has been proven dispensable for HSC. However, the BMP type-II receptor (BMPR-II) is highly expressed in HSC, leaving the possibility that BMP function via alternative pathways. Here, we establish that BMP signaling is required for self-renewal of adult HSC. Through conditional knockout we show that BMPR-II deficient HSC have impaired self-renewal and regenerative capacity. BMPR-II deficient cells have reduced p38 activation, implying that non-SMAD pathways operate downstream of BMP in HSC. Indeed, a majority of primitive hematopoietic cells do not engage in SMAD-mediated responses downstream of BMP in vivo. Furthermore, deficiency of BMPR-II results in increased expression of TJP1, a known regulator of self-renewal in other stem cells, and knockdown of TJP1 in primitive hematopoietic cells partly rescues the BMPR-II null phenotype. This suggests TJP1 may be a universal stem cell regulator. In conclusion, BMP signaling, in part mediated through TJP1, is required endogenously by adult HSC to maintain self-renewal capacity and proper resilience of the hematopoietic system during regeneration.</p>}},
  author       = {{Warsi, Sarah and Blank, Ulrika and Dahl, Maria and Min Grahn, Tan Hooi and Schmiderer, Ludwig and Andradottir, Silja and Karlsson, Stefan}},
  issn         = {{0390-6078}},
  language     = {{eng}},
  number       = {{8}},
  pages        = {{2203--2214}},
  publisher    = {{Ferrata Storti Foundation}},
  series       = {{Haematologica}},
  title        = {{BMP signaling is required for postnatal murine hematopoietic stem cell self-renewal}},
  url          = {{http://dx.doi.org/10.3324/haematol.2019.236125}},
  doi          = {{10.3324/haematol.2019.236125}},
  volume       = {{106}},
  year         = {{2021}},
}