# Mitochondria mediated intercellular metabolic coupling in bone marrow regeneration

> **NIH NIH R01** · CINCINNATI CHILDRENS HOSP MED CTR · 2022 · $279,840

## Abstract

ABSTRACT
Hematopoietic stem and progenitor cell (HSPC) transplantation (HSCT) is routinely used for the
treatment of inborn errors. Ex vivo gene editing/therapy is becoming a successful tool for treatment of
patients with bone marrow (BM) failure (BMF) and immunodeficiencies. However, the complete
engraftment of HSC in these patients requires larger-than-expected cell doses and HSC transplantation
is useful in ameliorating bone diseases like osteogenesis imperfecta. These unexpected observations
have not been followed by a stringent mechanistic analysis.
Mitochondria are well known metabolic sensors that bridge transcriptional signatures and cellular
functions. The mitochondrial content of HSC is elevated but the preferential use of glycolysis and low
mitochondrial activity in HSC as supported by a large cohort of experimental data suggest that
mitochondrial respiration is more dispensable for HSC than for their cell progeny.
Our preliminary data indicate that mitochondrial transfer exists between hematopoietic cells and their
surrounding microenvironment with functional consequences on hematopoietic and mesenchymal
regeneration after myeloablation. Our data suggests the existence of refined configuration of the
mitochondrial fate defining the HSC and microenvironment fate in the regenerating bone marrow by
metabolic coupling controlled by two major molecular nodes. We hypothesize that HSPC mitochondria
transfer is required for metabolic coupling between HSPC and MSC/P of the BM. The goal of this
proposal is to define the mechanisms that control the mitochondrial content and transfer from
hematopoietic engrafting cells and their impact on BM mesenchymal regeneration. We will elucidate the
mechanisms of mitochondrial transfer in the BM niche and their functional relevance using genetic and
pharmacological tools of gain- and loss-of-function and enumeration and functional analysis of
biochemical consequences of the traffic of mitochondria in the HSC niche. The mitochondrial transfer
reprograms the metabolome of recipient BM MSC/P and this reprogramming is necessary for
mesenchymal proliferation and reconstitution of the mesenchymal niche of the BM as well as bone
regeneration of the BM after myeloablation. We will determine whether a) the negative regulator role of
Cx43 in mitochondrial transfer depends on cell-to-cell contact; b) the mitochondrial transfer from BM
HSPC to BM MSC/P induces metabolic reprogramming of the mesenchymal microenvironment
resulting in hematopoietic regeneration; and, c) the prevention of AMPK activation is required for BM
mesenchymal and hematopoietic regeneration. This proposal will provide light on the molecular basis of
hematopoietic-dependent mesenchymal regeneration after transplantation and will identify the role of
hematopoietic Cx43 and host AMPK activity on bone marrow metabolic coupling.

## Key facts

- **NIH application ID:** 10400955
- **Project number:** 5R01DK124115-03
- **Recipient organization:** CINCINNATI CHILDRENS HOSP MED CTR
- **Principal Investigator:** Jose A. Cancelas
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $279,840
- **Award type:** 5
- **Project period:** 2020-07-01 → 2023-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10400955

## Citation

> US National Institutes of Health, RePORTER application 10400955, Mitochondria mediated intercellular metabolic coupling in bone marrow regeneration (5R01DK124115-03). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10400955. Licensed CC0.

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