Linheng Li, PhD
Faculty, The Graduate School of the Stowers Institute for Medical Research
Co-leader, Cancer Biology, The University of Kansas Cancer Center
Professor, Department of Pathology & Laboratory Medicine, University of Kansas School of Medicine

BS, Biology, Fudan University, Shanghai, P.R. China
MS, Molecular and Cellular Biology, New York University Medical School
PhD, Molecular and Cellular Biology, New York University Medical School

Areas of Interest 
Stem Cells and Niche, Regeneration, Cancer Treatment Resistance

Linheng Li, PhD, was finishing his doctoral studies in molecular and cellular biology when he came across an intriguing magazine article describing the new frontier of stem cell research, and how these  remarkable self-renewing cells could provide replacements for the worn-out or damaged cells of the blood, gut, skin, and other organs and tissues of the body. “It was a turning point in my career,” Li remembers. “I knew I wanted to learn more about these amazing cells.”

Among the first scientists appointed to the Stowers faculty, Li today is an internationally recognized leader on the biology of adult stem cells and the specialized niches that harbor stem cells in many organs and tissues of humans and other mammals. His lifelong passion for science was sparked by a book series he read during his childhood in China, titled Ten Thousand Unknown Questions. “It opened my mind and got me thinking about mysteries and how to solve them,” Li says.

Li went on to study biology and genetics at Fudan University in Shanghai. After receiving his BS degree at Fudan, he moved to New York to pursue his PhD at New York University under the guidance of Edward Ziff, PhD. There, Li investigated the Myc oncogene, and discovered a new function of Myc – to repress, rather than activate, genes that instruct cells to specialize and halt their growth. NYU awarded Li a PhD degree in molecular and cellular biology in 1995. For his postdoctoral fellow training, he joined the laboratory of Leroy Hood, PhD, the “father” of automatic DNA sequencing, at University of Washington. In collaboration with Irv Weissman, PhD, at Stanford University, Li explored the mysterious stem cells by searching what specific genes expressed in stem cells via large scale sequencing. He joined the Stowers Institute in 2000.

Li is glad he took a chance in 2000 on the brand-new research organization and established his lab at the Stowers Institute. He and his research have thrived in the Institute’s unique environment. “Stowers provides one of the best support systems for a scientist, not just financially, but also technologically and culturally,” he says.

Li also is an active member of the Kansas City community. He serves as liaison between the Stowers Institute and The University of Kansas Cancer Center and co-leads the center’s cancer biology program. Outside of work, Li enjoys playing tennis with his son, daughter, or colleagues at the KC Racquet Club, spending time with his wife, Xi (CiCi) He, and family hiking, visiting local art exhibits, attending concerts, and traveling.

Research Summary 

The Li Lab focuses on the hematopoietic (blood-forming) and intestinal systems to study stem cell development. Hematopoietic stems cells (HSCs) and intestinal stem cells (ISCs) are essential to the healthy functioning of the human body. These cells renew themselves and while HSCs differentiate into other cells, including white blood cells, red blood cells, and platelets, ISCs give rise to all types of intestinal epithelial cells for nutrient absorption, pathogen defense, and communication with the brain.

Li Lab is working to understand how microenvironmental (niche) signals or intrinsic genetic/epigenetic mechanisms regulate stem cell proliferation and differentiation in the hematopoietic and intestinal systems. They’re also looking at how glitches or changes in these systems are associated with human diseases such as leukemia and colon cancer.

An important first step was their discovery of the hematopoietic stem cell niche (the microenvironment where stem cells live), the first mammalian stem cell niche to be identified at the cellular level. The niche concept was a frame-shifting event and in the following decades, many different types of niches were discovered in bone marrow as well as in other organs. Later work by Li and others identified additional signals that promote self-renewal, including Wnt and PI3K-Akt, and explained how megakaryocytes (“mega” cells found in bone marrow), the Hoxb cluster of genes, and the genetic locus Dlk1-Gtl2, play critical roles in regulating HSCs.

Another research milestone was the discovery of two sub-populations of blood forming cells, one active and one quiescent or waiting to become active – a kind of reserve population. “It’s a back-up system. Very similar to how cars have a spare tire,” Li explains. The finding has implications for cancer treatment because tumors also contain active stem cells and a reservoir of quiescent backup cells, which may help explain why some tumors may become resistant to treatment. Indeed, Li’s lab made a seminal discovery in 2020 that abnormal activation of Wnt and PI3K-Akt empowers leukemia stem cell drug-resistance and immune escape, in which beta-catenin, a downstream effector of Wnt signaling, can directly regulate multiple immune-checkpoint genes.

Subsequently in 2021, Li’s lab reported identification of therapy refractory tumor-initiating stem cells (TrTSC) in intestinal adenoma and uncovered that TrTSC shapes its microenvironment into an immunosuppressive barrier and a pro-tumorigenic niche.

What’s next for Li and his research? “Stem cell biology is the base for regenerative medicine as well as a key to understanding cancer. I think in my life, the next five or ten years, we will help translate what we discovered into clinical settings, including the ability to expand “good” or healthy blood-forming stem cells and target “bad” or cancer stem cells, both of which involve the niche concept,” he says.

Featured Publications 
He X, Smith SE, Chen S, Li H, Wu D, Meneses-Giles PI, Wang Y, Hembree M, Yi K, Zhao X, Guo F, Unruh JR, Maddera LE, Yu Z, Scott A, Perera A, Wang Y, Zhao C, Bae K, Box A, Haug JS, Tao F, Hu D, Hansen DM, Qian P, Saha S, Dixon D, Anant S, Zhang D, Lin EH, Sun W, Wiedemann LM, Li L. Cell Rep. 2021;36:109674.doi: 10.1016/j.celrep.2021.109674.
Perry JM, Tao F, Roy A, Lin T, He XC, Chen S, Lu X, Nemechek J, Ruan L, Yu X, Dukes D, Moran A, Pace J, Schroeder K, Zhao M, Venkatraman A, Qian P, Li Z, Hembree M, Paulson A, He Z, Xu D, Tran TH, Deshmukh P, Nguyen CT, Kasi RM, Ryan R, Broward M, Ding S, Guest E, August K, Gamis AS, Godwin A, Sittampalam GS, Weir SJ, Li L. Nature Cell Biology. 2020 April 20: (22) 689–700. doi: 10.1038/s41556-020-0507-y
Zhao M, Tao F, Venkatraman A, Li Z, Smith SE, Unruh J, Chen S, Ward C, Qian P, Perry JM, Marshall H, Wang J, He XC, Li L. Cell Rep. 2019;26(3):652-69.e6. doi: 10.1016/j.celrep.2018.12.093.
Qian P, De Kumar B, He XC, Nolte C, Gogol M, Ahn Y, Chen S, Li Z, Xu H, Perry JM, Hu D, Tao F, Zhao M, Han Y, Hall K, Peak A, Paulson A, Zhao C, Venkatraman A, Box A, Perera A, Haug JS, Parmely T, Li H, Krumlauf R, Li L. Cell Stem Cell.2018;22:740-754 e747.
Li Z, Qian P, Shao W, Shi H, He XC, Gogol M, Yu Z, Wang Y, Qi M, Zhu Y, Perry JM, Zhang K, Tao F, Zhou K, Hu D, Han Y, Zhao C, Alexander R, Xu H, Chen S, Peak A, Hall K, Peterson M, Perera A, Haug JS, Parmely T, Li H, Shen B, Zeitlinger J, He C, Li L. Cell Res.2018. Author Correction: Cell Res 2018:1-14. Published online July 2018.;28:904-917
Qian P, He XC, Paulson A, Li Z, Tao F, Perry JM, Guo F, Zhao M, Zhi L, Venkatraman A, Haug JS, Parmely T, Li H, Dobrowsky RT, Ding WX, Kono T, Ferguson-Smith AC, Li L. Cell Stem Cell. 2016;18:214-228. Original Data | Journal Cover | Featured in: Serrano-Lopez J, Cancelas JA. Mom Knows Best: Imprinted Control of Hematopoietic Stem Cell QuiescenceCell Stem Cell.2016;18:158-160.

The University of Kansas Cancer Center Director’s William Jewel Team Science Award

The University of Kansas Cancer Center Director’s Outstanding Basic Science Award

Fellow, American Gastroenterological Association

Fellow, American Association for the Advancement of Science

Basil O’Connor Scholar

Hudson Prize

Award for Excellence in Life Science, Missouri Biotechnology Association

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