Kidney Week

Abstract: TH-OR078

Cell-Based Therapy and Podocyte Cell Fusion Rescue Type IV Collagen Composition in Alport Syndrome

Session Information

• Glomerular Diseases: Fibrosis and Extracellular Matrix
  November 07, 2019 | Location: Salon C, Walter E. Washington Convention Center
  Abstract Time: 04:30 PM - 04:42 PM

Category: Glomerular Diseases

• 1201 Glomerular Diseases: Fibrosis and Extracellular Matrix

Authors

• Lebleu, Valerie, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States

Valerie Lebleu, PhD



Dr. LeBleu received a PhD in Cell Biology from Harvard University, Boston, MA. Her research interests include collagen biology, extracellular matrix, fibrotic remodeling of tissues, epithelial plasticity, exosomes biology, and tumor microenvironment and metastasis.

• Alge, Joseph, Baylor College of Medicine, Houston, Texas, United States

Joseph Alge,

• Lovisa, Sara, MD Anderson Cancer Center, Houston, Texas, United States

Sara Lovisa,

• Kim, Jiha, North Dakota State University, Fargo, North Dakota, United States

Jiha Kim,

• Chen, Yang, UT-MD Anderson Cancer Center, Houston, Texas, United States

Yang Chen,

• Kanasaki, Keizo, Kanazawa Medical University, Kahoku, ISHIKAWA, Japan

Keizo Kanasaki,

• Teng, Yingqi, Beijing Reciproca Pharmaceuticals Co. Ltd., Beijing, China

Yingqi Teng,

• Gerami-Naini, Behzad, Tufts University, Boston, Massachusetts, United States

Behzad Gerami-Naini,

• Sugimoto, Hikaru, MD Anderson Cancer Center, Houston, Texas, United States

Hikaru Sugimoto,

• Kato, Noritoshi, Nagoya University, Nagoya, Japan

Noritoshi Kato,

• Revuelta, Ignacio, Hospital Clinic. Barcelona, Barcelona, Spain

Ignacio Revuelta,

• Miller, Caroline A., Indiana University, Indianapolis, Indiana, United States

Caroline A. Miller,

• Grau, Nicole, Heidelberg University Hospital, Heidelberg, Germany

Nicole Grau,

• Sleeman, Jonathan, Heidelberg University, Mannheim, Germany

Jonathan Sleeman,

• Rafii, Shahin, Cornell, New York, New York, United States

Shahin Rafii,

• Kalluri, Raghu, University of Texas MD Anderson Cancer Center, Houston, Texas, United States

Raghu Kalluri,

Background

Loss of function mutations in the genes encoding either of the three chains of type IV collagen forming the a3/a4/a5 protomer (COL4A3,COL4A4, and/or COL4A5genes) in Alport syndrome (AS) compromise the glomerular basement membrane (GBM) integrity and filtration function. Potential cure relies on restoring the missing chain(s) of type IV collagen; and cell-based therapies successfully delayed renal failure in mouse models of AS (Col4a3^KO).

Methods

To guide the development of cell-based therapies for AS, novel genetically engineered mouse models (GEMMs) were generated and used to define which glomerular cell(s) presents with rate-limiting function in GBM type IV collagen synthesis.

Results

In the new GEMMs, conditional deletion of Col4a3gene (Col4a3^cKO), following its breeding with a constitutively expressed Cre-recombinase transgene (CMV-Cre), proved functional and phenocopied the renal disease observed in Col4a3^KO mice. Using endothelial cells (Cdh5-Cre) and podocytes (Podocin-Cre) transgenics, we find that podocytes, in contrast with endothelial cells, are requisite for functional type IV collagen GBM composition in AS. Exogenously administered cells (bone marrow derived-, embryonic, and induced-pluripotent stem cells (iPSC)) rescue the renal phenotype in AS mice by restoring a functional GBM a3/a4/a5 type IV collagen composition. Using lineage-tracing genetic strategies, we uncovered that cell-based therapies ensues from the formation of a heterokaryon with recipient podocytes and rescues GBM type IV collagen composition in AS mice.

Conclusion

Such fusion-dependent tissue regeneration was associated with TGFb1-dependent genetic reprogramming of the injured kidney glomerular cells and required de novo synthesis of the missing type IV collagen by the fused stem cells. These experiments highlight cell fusion as a mechanistic driver of stem cell-induced tissue regeneration.