Human induced pluripotent stem cells improve visual acuity, vascular
health
Date:
March 10, 2022
Source:
Indiana University School of Medicine
Summary:
Researchers are investigating novel regenerative medicine approaches
to better manage vascular health complications from type 2 diabetes
that could someday support blood vessel repair in the eye among
diabetic patients with early retinal vascular dysfunction.
FULL STORY ========================================================================== Researchers at Indiana University School of Medicine, in collaboration
with the University of Alabama at Birmingham and five other institutions,
are investigating novel regenerative medicine approaches to better
manage vascular health complications from type 2 diabetes that could
someday support blood vessel repair in the eye among diabetic patients
with early retinal vascular dysfunction. These research strategies
include identifying and using new methods to differentiate or mature
human induced pluripotent stem cells (hiPSCs) into the specific mesoderm
subset of cells that display vascular reparative properties.
========================================================================== "Vascular diseases afflict hundreds of millions of people in the world,"
said Chang-Hyun Gil, MS, PhD, a postdoctoral fellow in the Department
of Surgery and co-first author of the study. "In this study, we focused
on the retinal vessel in type 2 diabetes. Our results demonstrate the
safe, efficient and robust derivation of hiPSC-derived specific mesoderm
subset for use as a novel therapy to rescue ischemic tissues and repair
blood vessels in individuals with vascular diseases. The results provide
a foundation for an early phase clinical trial." In the multi-site,
early phase study recently published in Science Advances, investigators genetically reprogrammed diabetic and non-diabetic peripheral blood cells
into hiPSCs and matured the cells into special blood vessel reparative
cells. Upon injection into animal models with type 2 diabetic murine
(T2D) retinal dysfunction, results showed significant improvement
in visual acuity and electroretinograms with restoration of vascular
perfusion. They hypothesized hiPSC-derived vascular reparative cells
may serve as a source of endothelial precursors that will display in
vivo vessel reparative properties in these diabetic subjects.
"Unlike the use of embryonic stem cells (ESCs), genetically engineered
hiPSCs do not carry the ethical challenges ESCs possess that limit their possible usage, and hiPSCs are being increasingly recognized as a viable alternative in study design and application as a cell therapy for human disorders," Gil said.
According to the U.S. Centers for Disease Control and Prevention,
more than 37 million people in the United States have diabetes-more
than 11 percent of the U.S. population. What's more, diabetes-related complications have risen among both young adults ages 18 to 44 years of
age and adults ages 45 to 64. These complications cause major metabolic disturbances that damage the cardiovascular, visual, peripheral nerve
and renal systems through harming small and large microvessels that feed
these tissues. In 2019, more than 11 percent of adults ages 18 and older reported severe vision issues or blindness and more than 1.87 million
adults were diagnosed with major cardiovascular disease.
"This work by Dr. Gil represents a monumental step forward in
the application of induced pluripotent stem cells in treating the
complications of diabetes," said Michael P. Murphy, MD, the Cryptic
Medical Research Foundation Professor of Vascular Biology Research at IU
School of Medicine, a vascular surgeon at IU Health and Eskenazi Health
and a coauthor of the study.
Researchers converted hiPSC into a specific mesoderm subset that was
enriched to generate endothelial cells with vessel reparative properties similar to endothelial colony forming cells (ECFC). Endothelial cells
are cells found in the inner lining of blood vessels, lymph vessels and
the heart and are a major component in regulating vascular function and inflammatory reactions.
Endothelial cells control blood flow and regulate the transfer of proteins
from blood into tissues.
Gil said the specific mesoderm subset expressing KDR, NCAM1 and APLNR
(KNA+ mesoderm) exhibits enhanced capacity to differentiate into ECFC
and form functional blood vessels in vivo and that mesoderm populations
correct vasodegeneration of injured retinal vessels. Electroretinograms indicate enhanced function of neural retina and optokinetic nystagmus
studies show improved vision.
"The next translational step of the work is to transfer the research
protocols reported for differentiation of the hiPSC into to S-KNA+ cells
into large scale manufacturing processes," said Mervin C. Yoder, MD, distinguished professor emeritus and research advisor for the Indiana
Center for Regenerative Medicine and Engineering. Yoder is another
coauthor of the study and is the scientific founder of Vascugen, a company driven to advance treatments for life- threatening conditions caused
by microvascular conditions. "Selected aspects of this work have been
licensed by Vascugen, Inc., through the Indiana University Innovation
and Commercialization Office, who are focused on developing vascular
reparative cells from induced pluripotent stem cells." Another study
coauthor is Maria B. Grant, MD, the former Marilyn Glick Professor of Ophthalmology at the IU School of Medicine Eugene and Marilyn Glick Eye Institute and current endowed chair of ophthalmology at UAB. Grant said
this is a highly translational study that is a continuation of a grant
she and Yoder have been working on for the last 20 years regarding stems
cells and how they can be used to repair blood vessels in the eye. While
hiPSCs can take a long time to grow, the study team simplified the process
to shorten the time to grow them and make them more feasible to translate
into a human therapy to repair blood vessels in the eye.
"At UAB, we took the stem cells and hiPSC cells and studied them,"
she said.
"Science is really team science. I bring all the eye experience and
some stem cell experience, and Dr. Yoder brings a lot of stem cell
experience. It's a complementary collaboration." "I want to express my greatest thanks to Dr. Yoder, Dr. Grant and Dr. Murphy for their support,"
Gil said. He will remember Yoder for "his dedication, passion, patience
and kindness" and Murphy for supporting him in completing the study.
========================================================================== Story Source: Materials provided by
Indiana_University_School_of_Medicine. Note: Content may be edited for
style and length.
========================================================================== Journal Reference:
1. Chang-Hyun Gil, Dibyendu Chakraborty, Cristiano P. Vieira,
Nutan Prasain,
Sergio Li Calzi, Seth D. Fortmann, Ping Hu, Kimihiko Banno, Mohamed
Jamal, Chao Huang, Micheli S. Sielski, Yang Lin, Xinxin Huang,
Mariana D.
Dupont, Jason L. Floyd, Ram Prasad, Ana Leda F. Longhini, Trevor J.
McGill, Hyung-Min Chung, Michael P. Murphy, Darrell N. Kotton,
Michael E.
Boulton, Mervin C. Yoder, Maria B. Grant. Specific mesoderm subset
derived from human pluripotent stem cells ameliorates microvascular
pathology in type 2 diabetic mice. Science Advances, 2022; 8 (9)
DOI: 10.1126/sciadv.abm5559 ==========================================================================
Link to news story:
https://www.sciencedaily.com/releases/2022/03/220310170834.htm
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