When it comes to heart disease, most people are no strangers to it. Academic giant Ji Xianlin, music legend Michael Jackson, Yang Jie—the director of the 1986 version of "Journey to the West"—and renowned sketch comedian Gao Xiumin all passed away due to heart-related causes.

Cardiovascular disease has become the leading cause of death worldwide. According to the "China Cardiovascular Disease Report 2018," published by the National Center for Cardiovascular Diseases, China has 11 million patients with coronary heart disease, 5 million with pulmonary heart disease, 4.5 million with heart failure, 2.5 million with rheumatic heart disease, and 2 million with congenital heart disease—figures that continue to rise annually, both in terms of new cases and fatalities. As a result, heart disease remains one of the critical areas of focus in medical research.

Mesenchymal stem cells are emerging as a rising star in heart disease treatment.

The ability of stem cells and progenitor cells to stimulate heart regeneration has been studied for nearly two decades. Through research on surface markers, differentiation potential, and the identification of growth factors secreted by various cell types, bone marrow mesenchymal stem cells (MSCs) have emerged as particularly promising candidates. An increasing body of evidence now supports the safety and efficacy of this approach.

Recently, *Stem Cell Translational Medicine* published the article "Concise Review: Rational Use of Mesenchymal Stem Cells in the Treatment of Ischemic Heart Disease" [1], which compiles a comprehensive overview of ongoing global clinical trials investigating mesenchymal stem cell therapies for heart disease. The review highlights that bone marrow-derived mesenchymal stem cells (MSCs) have been shown to possess remarkable regenerative capabilities, exerting their effects through multiple mechanisms—including differentiation into mesodermal lineages, immunomodulation, paracrine signaling, and the secretion of exosomes and microvesicles (which themselves carry potent angiogenic cytokines or mRNA molecules). These processes collectively facilitate local microenvironment modulation, ultimately promoting myocardial cell repair, regeneration, and remodeling of the cardiac ventricles.

Scientific research has confirmed that mesenchymal stem cells can differentiate into a variety of cell types, including osteoblasts, adipocytes, skeletal muscle cells, pancreatic islet cells, and cardiomyocytes. Moreover, mesenchymal stem cells have been shown to be capable of being transplanted into the body and transforming into cardiomyocytes, thereby repairing infarcted heart tissue.

1. Initially, the mechanism by which mesenchymal stem cells promote heart regeneration was thought to involve differentiating into cardiomyocytes to replace necrotic contractile heart tissue. However, as research has advanced, scientists have discovered that the paracrine mechanisms of mesenchymal stem cells may actually play a more significant role than their ability to differentiate into cardiomyocytes and replace dead cells—whether through paracrine signaling or signals delivered via vesicles or endosomes. In essence, these mechanisms help enhance cardiomyocyte survival, reduce inflammation, and protect overall cardiac function.

2. Mesenchymal stem cells can secrete a variety of cytokines and growth factors, helping to modulate the microenvironment in ischemic and hypoxic focal areas. Paracrine factors released by mesenchymal stem cells may exert pleiotropic effects on cardiac tissue—promoting local angiogenesis, stimulating cardiac progenitor cells, and reducing cardiomyocyte apoptosis.

3. Figure 1: Shows preliminary research on how bone marrow mesenchymal stem cells influence cardiac regeneration mechanisms.

Figure 1: Mechanisms of MSC-mediated cardiac regeneration. The initially reported mechanism by which MSCs promote heart regeneration involves replacing necrotic, contractile myocardial tissue with differentiated cardiomyocytes (left side of the figure). However, this mechanism likely contributes relatively little, while paracrine signaling—whether through secreted paracrine factors or signals packaged within microvesicles or exosomes—plays a much larger role (right side of the figure). Together, these processes enhance cardiomyocyte survival, reduce inflammation, and help preserve cardiac function. Abbreviations: CM – conditioned medium; MSC – mesenchymal stem cells; SMC – smooth muscle cells.

4. Figure 2: Illustrates the research on the ideal cell type for cell transplantation [2].

Figure 2: (1) To date, most cardiac regeneration approaches in clinical trials have involved transplanting or infusing cells with potential progenitor characteristics into the infarcted myocardium. (2) Stem cell types used for exogenous delivery include embryonic stem cells, induced pluripotent stem cells, and adult progenitor cells (such as cardiac, bone marrow, and skeletal muscle-derived myoblasts). (3) While some rigorously designed and well-executed studies have shown promising signals of benefit, there is still no consensus on the ideal cell type for cell transplantation. Ultimately, bone marrow-derived mesenchymal stem cells stand out as the preferred option due to their autologous nature, rapid ex vivo expansion capabilities, and ability to differentiate into cardiomyocytes.

Heart failure is currently a major cause of death from cardiovascular disease, and existing treatments can only slow down the progression of the illness. Laboratory experiments and recent clinical trials have shown that cell-based therapies hold promise in improving heart function, sparking tremendous excitement about their potential to drive cardiac regeneration. As we know, timely reperfusion of the heart can save more patients—yet cell therapy may not only prevent, but even reverse the advancement of heart failure itself.

The 2015 December article titled "Application of Stem Cell Therapy in Cardiovascular Disease: Current Status," published on ResearchGate, highlights that bone marrow-derived progenitor cells and other progenitor cell types can differentiate into vascular cell types, thereby restoring blood flow. Similar applications are currently being evaluated for coronary artery disease and acute coronary syndrome, where the underlying mechanisms of vascular regeneration have already been thoroughly validated [3], as illustrated in Figure 3. These groundbreaking discoveries are igniting a new revolution in the field of cardiac therapy.

Figure 3: (1) Injecting cultured cells into the myocardium or coronary arteries for cell-based therapy; (2) Utilizing tissue engineering approaches to combine cells with biomaterials, creating functional tissue constructs outside the body for transplantation directly into the heart; (3) Reprogramming non-cardiac cells into cardiomyocytes in situ—achieved using viruses, small molecules, or microRNAs; (4) Employing small molecules such as growth factors or microRNAs to promote wound healing by enhancing cardiomyocyte proliferation or angiogenesis.

In a trial investigating functional regeneration enhancement in patients with non-ischemic cardiomyopathy [4], it was also demonstrated that, following treatment, both the extent (Figure 4A) and severity (Figure 4B) of left ventricular dysfunction significantly decreased as regional wall motion improved in the target area. Overall, the left ventricular ejection fraction increased by an absolute 3.2 ± 4.1 (Figure 4C).

Figure 4: Individual changes in the sedentary area (A), severity of sedentary behavior (B), and ejection fraction (C) between baseline and the 3-month follow-up.

The study demonstrated that, in 9 patients undergoing quantitative analysis (cardiac MRI), MRI-derived LVEF increased from 32.3 ± 9.2% to 36.7 ± 9.7% (P = 0.011). Additionally, end-systolic left ventricular volume decreased from 90 ± 53 mL/m² to 76 ± 50 mL/m² (P = 0.066), while end-diastolic left ventricular volume remained unchanged—measuring 127 ± 61 mL/m² at baseline and 114 ± 56 mL/m² at follow-up (P = 0.110).

Additionally, dilated cardiomyopathy (DCM) is also the most common non-ischemic cardiomyopathy worldwide, often leading to ventricular dilation, myocardial cell death, thinning of the ventricular walls, and fibrosis. Despite ongoing challenges in clinical outcomes, stem cell therapy has demonstrated excellent safety profiles and shown promising signs of clinical improvement [5,6]. In an analysis of eight randomized controlled trials involving a total of 531 participants [7], researchers found that stem cell treatment significantly improved left ventricular ejection fraction (Figure 5), reduced left ventricular end-systolic volume (Figure 6), and decreased left ventricular end-diastolic volume size (Figure 7).

Figure 5: Forest plot showing LVEF in stem cell therapy patients with dilated cardiomyopathy versus the control group

Figure 6: Forest plot showing left ventricular end-systolic volume (LVESV) in stem cell-treated patients with dilated cardiomyopathy versus the control group

Figure 7: Forest plot comparing left ventricular end-diastolic circumference (LVEDC) in stem cell-treated patients with dilated cardiomyopathy versus the control group.

Global Summary of Clinical Trials on Bone Marrow Mesenchymal Stem Cell Therapy for Heart Disease

In fact, as early as 2006, a task force from the European Society of Cardiology (ESC) reached a consensus on whether autologous cell therapy could be used to treat DCM. That same year, the first human clinical trials were reported. Today, there are over 21 clinical trials registered globally on the clinicaltrials.gov website investigating autologous or allogeneic bone marrow mesenchymal stem cell therapies for heart diseases, with specific indications including acute myocardial infarction, ischemic heart disease, heart failure, and dilated cardiomyopathy. Notably, the vast majority of these trials are currently in Phase II.

Summary of Clinical Trials on Autologous/Allogeneic Bone Marrow Mesenchymal Stem Cell Therapy for Heart Disease

Note: Specific project information listed in the table can be verified by using the corresponding identifier on the clinicaltrials.gov website.

The future looks promising: Ischemia-tolerant human bone marrow mesenchymal stem cells (it-hMSC)

Jiuzhitang Maker's U.S. partner, Stemedica, has developed its clinically validated cell-production platform, BioSmart™, at its cGMP-compliant facility in California. This platform mimics the natural microenvironment of cells within the human body and produces ischemia-tolerant human bone marrow mesenchymal stem cells (it-hMSCs) under continuous low-oxygen conditions. Compared to stem cells cultured in standard atmospheric oxygen levels, it-hMSCs exhibit significantly enhanced capabilities—whether in terms of proliferation, homing ability, tissue-repair potential, or inflammation-regulating functions. As illustrated below, it-hMSCs demonstrate heightened sensitivity to key cytokines involved in wound healing, such as EGF, bFGF, VEGF-121, IL-1β, IL-6, and TNF-α, enabling superior homing properties and positioning them as a powerful tool for advancing cardiac disease therapies.

On September 12, 2018, Kazakhstan’s Ministry of Health approved the medical technology using stem cells produced by Stemedica for the treatment of acute myocardial infarction, marking a significant milestone as Stemedica’s it-hMSC achieved a breakthrough toward market availability and officially entered clinical practice.

In 2019, Jiuzhitang Maker partnered with Kazakhstan’s ALTACO Company to jointly establish the Jiuzhitang-ALTACO International Medical Center at the China-Kazakhstan Khorgos International Border Cooperation Center, serving as an innovative collaboration platform for international stem cell research and clinical translation. The International Medical Center will focus its scientific research and translational studies on ischemia-tolerant mesenchymal stem cells developed by Stemedica.

As science and technology continue to advance, we believe that stem cell therapy will achieve even greater progress, offering new tools and hope for both medical professionals and heart disease patients worldwide.

References:

[1] Concise Review: Rational Use of Mesenchymal Stem Cells in the Treatment of Ischemic Heart Disease

[2] Application of Stem Cell Therapy in Cardiovascular Disease: Current Status

[3] Stem cells in heart failure management: What have we learned from clinical trials?

[4] A pilot trial to evaluate the potential effects of selective intracoronary infusion of bone marrow-derived progenitor cells in patients with nonischemic dilated cardiomyopathy: final 1-year results of the Transplantation of Progenitor Cells and Functional Regeneration Enhancement Pilot Trial in Patients with Nonischemic Dilated Cardiomyopathy.

[5] A safety and feasibility study of cell therapy in dilated cardiomyopathy

[6] Cell therapy in dilated cardiomyopathy

[7] Efficacy and safety of stem cell therapy in patients with dilated cardiomyopathy: a systematic review and meta-analysis