# Normalization of Sickle Cell Disease bone marrow niche defects by RBC transfusion

> **NIH NIH P01** · BOSTON CHILDREN'S HOSPITAL · 2022 · $858,450

## Abstract

Project Summary
To date, the only curative option for Sickle Cell Disease (SCD) is transplantation of allogeneic HSC. Recently,
clinical trials utilizing gene corrected autologous HSC have been initiated and hold much promise. However
significant limitations and challenges remain for HSC transplantation in SCD patients. In humanized SCD mice
we showed for the first time the pathologic impact of SCD on bone marrow (BM) vascular and perivascular
niches that are deemed critical to HSC transplantation and steady state hematopoiesis. Specifically, the
studies uncovered a disorganized and structurally abnormal BM neovascular network of increased numbers of
highly tortuous arterioles occupying the majority of the BM cavity, as well as fragmented sinusoidal vessels
filled with aggregates of erythroid and myeloid cells. Additionally, the number of CXCL12 producing
perivascular mesenchymal niche cells, was reduced thus further supporting a defective hematopoietic niche in
SCD mice. Further investigations provided a model of SCD BM, where slow RBC flow and vaso-occlusion
further diminish local oxygen availability in the physiologically hypoxic BM cavity. These events trigger an
angiogenic milieu conducive to aberrant vessel growth. Remarkably, the distorted neovascular network was
completely reversed by a 6 weeks of blood transfusion highlighting the plasticity of the vascular niche.
Additional, unpublished preliminary data indicate that long-term (16 weeks) HSC reconstitution when
transplanted into SCD mice is significantly compromised. Collectively, these studies have led us to hypothesize
that impaired engraftment of HSPCs into SCD BM is caused by structural and functional abnormalities of the
hematopoietic vascular and/or mesenchymal niche; and that correction of key vascular niche cell defects will
improve HSPC engraftment. Stem cell mobilization may also be affected by the BM niche and we will seek to
understand how stem cells egress from the BM to the blood in SCD. Thus three aims are proposed to test
these hypotheses: 1. to define the SCD niche defects at the molecular and cellular level in humanized SCD
mouse 2. to determine which niche defects are normalized by blood transfusion and define the BM niche
defects in patients; and 3. to ascertain the link between BM niche defects and impaired HSCP engraftment.
Collectively, these investigations will help optimize approaches towards efficient and long-term hematopoietic
engraftment in the context of curative therapies.

## Key facts

- **NIH application ID:** 10494383
- **Project number:** 1P01HL158688-01A1
- **Recipient organization:** BOSTON CHILDREN'S HOSPITAL
- **Principal Investigator:** JOHN P MANIS
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $858,450
- **Award type:** 1
- **Project period:** 2022-08-15 → 2027-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10494383

## Citation

> US National Institutes of Health, RePORTER application 10494383, Normalization of Sickle Cell Disease bone marrow niche defects by RBC transfusion (1P01HL158688-01A1). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10494383. Licensed CC0.

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