Official websites use .gov

A .gov website belongs to an official government organization in the United States.

Secure .gov websites use HTTPS

A lock ( 🔒 ) or https:// means you've safely connected to the .gov website. Share sensitive information only on official, secure websites.

Need Help

The origin and fate of Adipo-CAR cells in Pth1r-OsxKO mice

Award Number: R21AR088224
ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/10/2026
PERIOD OF PERFORMANCE END DATE: 08/31/2028

Group Awards By:

View Award Description

The origin and fate of Adipo-CAR cells in Pth1r-OsxKO mice - PROJECT SUMMARY Skeletal fragility due to low bone mass in osteoporosis causes fractures in 50% of women and 25% of men over age 50. Reduced bone mass is accompanied by increased marrow fat. Elucidating a common mechanism for fat and bone mass changes may lead to clinically relevant targets for osteoporosis treatment. Within the bone microenvironment both bone-forming osteoblasts and fat-laden adipocytes are derived from mesenchymal stem cells (MSCs). MSC fate relies in part on parathyroid hormone receptor (PTH1R) signaling. Conditional knockout (cKO) of Pth1r in Osterix (Osx)-expressing osteoprogenitors in mice results in severe bone loss while cKO of Pth1r in Prx1-expressing mesenchymal progenitors leads to decreased bone plus increased marrow fat. However, how PTH1R signaling influences mesenchymal lineage allocation remains incompletely understood. Advancements in single-cell RNA-sequencing (scRNA-seq) and lineage tracing have enhanced our understanding of mesenchymal populations and identified Osteo- and Adipo- “CXCL12- abundant reticular” (CAR) cells. We have discovered a significantly expanded Adipo-CAR population in Pth1r- OsxKO mouse bone. However, the origin and fate of Adipo-CAR cells are not clear. Preliminary CytoTRACE analysis suggests that Adipo-CAR cells are more differentiated than their mesenchymal progenitors and Osteo- CAR cells. To clarify the relationship between Osx+ progenitors, Osteo-CAR, and Adipo-CAR populations, we will use DNA barcoding for in vivo lineage tracing. This innovative approach overcomes limitations of classical lineage tracing including inability to distinguish overlapping populations or determine cell origin, and technical difficulty with complex multi-allele crosses. Based on our preliminary and published data we hypothesize PTH1R governs the fate switch between Osteo-CAR and Adipo-CAR populations. In Specific Aim 1 we will optimize DNA barcoding-based lineage tracing in the bone microenvironment. Using the CellTag DNA barcoding system coupled to scRNA-seq analysis we will perform lineage tracing in vitro with cultured bone marrow-derived mesenchymal cells and pilot in vivo lineage tracing in Control [Osx+:GFP:Cre] and wildtype (WT) mice. We predict that we will successfully integrate the CellTag system into our models for lineage tracing in the bone microenvironment. In Specific Aim 2 we will determine if expanded Pth1r-OsxKO Adipo-CAR cells are derived from Osx+ progenitors and give rise to adipocytes. We will implement our optimized CellTag protocol to transduce Pth1r-OsxKO:tdTomato (KO) and PTH1R-OsxWT:tdTomato (Control) mice via intratibial injection for scRNA-seq and lineage tracing analysis, and image KO and Control mouse femurs to validate Adipo-CAR cell accumulation and localization. We predict Adipo-CAR cells are elevated due to re-allocation of Osx+ progenitors and in turn give rise to more adipocytes. Understanding MSC lineage hierarchies is crucial to define the signaling pathways that cooperatively regulate marrow fat accumulation and bone loss.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $200,478 )
2026	2026	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	1	9/3/2026	NEW	$200,478
														Subtotal = $200,478

Grand Total All Awards = $200,478

Top

All Categories

About

Search

Reports

Data Submission

Award Information

The origin and fate of Adipo-CAR cells in Pth1r-OsxKO mice

Award Number: R21AR088224

ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 09/10/2026

PERIOD OF PERFORMANCE END DATE: 08/31/2028

Federal Websites

Department of Health & Human Services

HHS Operating Divisions

HHS Staff Divisions

Download A Document Viewer